30 34 · michael abanto verstärkt seit dem 1. juni 2012 die biooptik-facility an der hebelstrasse!...

Biomarkers, regulators and effectors of low-grade gliomainvasion | Survival, proliferation, deletion: ask the lymph

node stroma! | Wien ist anders 2 12

Periodisches Informationsblatt des Departementes BiomedizinUniversität Basel, Universitätsspital Basel undUniversitäts-Kinderspital beider Basel

DBM Facts 2|2012 Departement Biomedizin

RedaktionHeidi Hoyermann

ÜbersetzungenPaula Cullen

LayoutEric Spaety, Morf Bimo Print AG, Binningen

IT-UnterstützungNiklaus Vogt

AdministrationManuela Bernasconi

FotosMathias Mangold www.sublim.chFrank Neumann

TitelfotoStairway to the atlantic ocean, Shutterstock

DruckMorf Bimo Print AG, Binningen

AnschriftRedaktion DBM FactsDepartement BiomedizinHebelstrasse 204031 [email protected]

IMPRESSUM

Editorial 1Auszeichnungen /Congratulations 13/14Publikationen /Publications 15Art 21Mitarbeitende /Colleagues 22Informatik /Informatics

36

Urlaubslektüreempfohlen von DBM Mitarbeitenden

Survival, proliferation,deletion: ask the lymph node stroma!from Simona Rossi Girard

Triathlonfrom Brynn Kvinlaug

Wien ist andersvon Denise Berger

Biomarkers, regulators andeffectors of low-grade gliomainvasionfrom Luigi Mariani

2

8 26

30 34

DBM Facts 2|2012 Department of Biomedicine

EDITORIAL

Peter Meier-AbtHead a.i.

Dear Readers

What news is there? Only positive news! On the 1st July 2012 Viola Heinzelmann will take up her position as

senior physician at the women's clinic and as research group leader at the DBM. Appointment negotiations are

underway with Prof. O. von Bohlen, the Professor of Haematology/Stem Cell Biology appointment report has

been accepted by the faculty. The long wait time for microscopy should be coming to an end: since the 1st of

June 2012 Michael Abanto has strengthened the bio-optic facility at Hebelstrasse! Roland Ivanek has begun with

the installation of bioinformatics at Mattenstrasse! We welcome them all and wish them every success!

In this summer issue Luigi Mariani and his co-workers share the most up to date knowledge about brain tumor

biology with us (page 2), Simona Rossi and her team introduce us to the Immunoregulation game (page 8), we

report on great achievements (page 13) and how simple and brilliant research can be (page 14). Brynn Kvinlaug

knows all about staying power, as a triathlete she does not stop, even in her free time (page 26). Denise Berger

does not stop either, as Vienna, her former chosen place of residence, challenges a person as a whole (page 30).

For those whom that is not yet enough, they are sure to find something to pass the time in the DBM book

reviews! Happy reading and enjoy the holidays!

Peter Meier-Abt

Liebe Leserinnen und Leser

Was gibt es Neues zu berichten? Nur Positives! Am 1. Juli 2012 nimmt Viola Heinzelmann ihre Tätigkeit als

leitende Ärztin in der Frauenklinik und Forschungsgruppenleiterin am DBM auf. Die Berufungsverhand-

lungen mit Prof. O. von Bohlen sind im Gange, der Berufungsbericht Professur Hämatologie/Stamm-

zellbiologie wurde von der Fakultät akzeptiert. Die langen Wartezeiten am Mikroskop haben ein Ende:

Michael Abanto verstärkt seit dem 1. Juni 2012 die Biooptik-Facility an der Hebelstrasse! Mit dem Aufbau

der Bioinformatik an der Mattenstrasse hat Roland Ivanek angefangen! Allen viel Erfolg und ein herzliches

Willkommen!

In der nun vorliegenden Sommerausgabe teilen uns Luigi Mariani und seine Mitarbeitenden die neuesten

Erkenntnisse aus der Brain Tumor Biology mit (ab Seite 2), führen uns Simona Rossi und ihr Team in das

Spiel der Immunoregulation ein (ab Seite 8), berichten wir von grossen Erfolgen (Seite 13) und davon, wie

einfach und genial Forschung sein kann (Seite 14). Durchhaltevermögen anderer Art beweist Brynn Kvin-

laug, die als Triathletin auch in der Freizeit nicht so schnell aufgibt (ab Seite 26). Das tut Denise Berger auch

nicht, fordert ihre ehemalige Wahlheimat Wien doch den ganzen Menschen heraus (ab Seite 30). Und wem

das noch nicht genug ist, der findet sicher unter den DBM Lesetipps den richtigen Zeitvertreib!

Viel Spass beim Lesen und schöne Ferien!

Peter Meier-Abt


2 WISSENSCHAFT | SCIENCE DEPARTEMENT BIOMEDIZIN HEBEL STRASSE

Biomarkers, regulators andeffectors of low-grade gliomainvasion

The group ‘Brain Tumor Biology’. From left to right. Standing: Archana Ramadoss, Marie-Françoise Ritz, Gregor Hutter, Luigi Mariani, Jean-Louis Boulay. Sitting: Severina Leu, Cristóbal Tostado, Elisabeth Taylor. Missing on the picture: Martin Sailer

Glioma progress by tumor cell invasion into adjacent brain tissue. The main goal of the Laboratory of Brain Tumor Biology is to understand mechanisms underlying tumor cell invasion. This involves the identification of biomarkers, genetic regulators, molecular networks and molecular effectors of tumor cell invasion that can ultimately be targeted to control glioma progression.


DEPARTMENT OF BIOMEDICINE HEBEL STRASSE WISSENSCHAFT | SCIENCE 3

Introduction

Gliomas are among the deadliest malignancies, with a

median survival varying between few months for the

most frequent malignant grade IV glioblastoma (GBM),

to over 20 years for the low-grade glioma (LGG). Given

the extremely high resistance of tumor cells to chemo-/

radiotherapy, conventional therapies have not signifi-

cantly improved patient survival. In addition, the high

invasive capacity of glioma cells into adjacent brain tis-

sue compromises total surgical resection. Besides grad-

ing, glial tumors are classified into histologic subtypes

based on morphologic and antigen expression features.

The finding of chromosomal alterations and gene muta-

tions allowed the identification of some glioma devel-

opmental pathways and refined classification into mo-

lecular subsets with various degrees of aggressiveness

or responsiveness to current therapies.

The research of the Laboratory of Brain Tumor Biology,

in close partnership with the Neurosurgery Clinic, fo-

cuses on glioma, and more specifically, on LGG. At the

clinical point of view, we aim at defining biomarkers to

classify LGG into molecular subsets to standardize treat-

ment strategies. At a more basic level, we aim at identi-

fying genetic regulators and molecular effectors of gli-

oma cell invasion. For both purposes, we are collecting

resected glioma biopsies of distinct grades and histolo-

gies directly in the operating room for further analytical

and experimental purposes.

Genotyping low-grade gliomas

In collaboration with Stephan Frank (Pathology, UHBS),

Stefanie von Felten (Clinical Trial Unit, UHBS), Istvan Vajtai

and Erik Vassella (University of Bern).

Based on histology, LGG have been divided into three

distinct subsets: diffuse astrocytoma (A), oligoastrocy-

toma (OA) and oligodendroglioma (OG). Molecular ge-

netic and genomic analyses of LGG have identified four

major alterations relevant to LGG development: IDH mu-

tations and MGMT gene promoter methylation in nearly

80% of LGG, and TP53 mutations and 1p/19q allelic loss,

each occurring in nearly 25% of LGG in a mutually exclu-

sive manner. IDH genes encode isocitrate dehydroge-

nase that normally catalyzes the conversion of isocitrate

into α-ketoglutarate (αKG) in the Krebs cycle. The muta-

Figure 1. Association between IDH mutation and favorable outcome in LGG patients.

imputed dataobserved data



tions create a novel catalytic function that converts αKG

into 2-hydroxyglutarate (2HG). Accumulation of 2HG

oncometabolite leads to genome-scale impaired DNA

demethylation that results in extensive methylome and

transcriptome remodelling, which includes methyla-

tion of the MGMT gene promoter. These are early events

in the course of gliomagenesis and provide a molecu-

lar basis for the co-segregation observed between IDH

mutation and MGMT methylation. Later, TP53 mutations

and 1p/19q allelic loss occur preferentially in A and OG,

respectively. We are currently analysing the impact of

these alterations on survival of >200 LGG in a retrospec-

tive study. In order to increase accuracy, missing data, a

major issue in retrospective studies, is being compen-

sated by multiple imputation.

Identification of novel biomarkers for gliomas

As depicted in Figure 2, glioma can be divided into 4 ma-

jor molecular groups based on genomic, transcriptomic

and proteomic/phosphoproteomic profiles: proneural

(includes LGG with IDH mutation, MGMT methylation or

PDGFRA amplification, derived anaplastic glioma and

GBM), classical (GBM that contain EGFR amplification/

mutation and CDKN2A loss), neural (GBM with additional

TP53 mutations), and mesenchymal (ultimate GBM de-

velopmental stage).

Upon surgical resection, we routinely extract DNA, RNA

and protein from tumor biopsies. This material is used

to attempt a systematic molecular classification of glio-

mas of all grades and histologies operated at the Neu-

rosurgical Clinic. In cases where biopsies are taken from

distinct areas of the tumor core and of the invasive rim

at tumor periphery, variations in RNA expression be-

tween these distinct areas of the same tumor will be

examined.

We are currently constructing a comprehensive, web-

based glioma patient database containing personal (de-

mographics, etiology, personal history); clinical (patient

outcome, survival); MRI imaging (tumor size, location

and infiltration grade), histopathological (tumor histol-

ogy and WHO grade) and molecular annotations (geno-

typing, transcriptome, proteome and activated signal-

Figure 2. Glioma classification based on genomic and genetic data. From Verhaak et al., Cancer Cell (2010) 17:98.



ing pathways). Classification of gliomas according to

histologic, molecular and invasive features, will allow

identification of novel glioma biomarkers, and hope-

fully identification of subgroups of glioma responsive

to customized therapies.

Isolation and ex vivo culture of glioma cells from

resected tumors

Parts of the resected tumors are also subjected to cell

dissociation for ex vivo cell culture. Glioma cells are then

grown ex vivo to establish long-term glioma stem cell

and differentiation cultures. Whenever possible, biop-

sies are taken from distinct areas of the tumor core and

of the invasive rim at tumor periphery to test their re-

spective invasive behaviours. Further, putative glioma

stem cells are xenografted orthotopically into the brains

of immunocompromized mice to assess their tumori-

genicity in vivo.

Molecular and genetic mechanisms of glioma

invasion

We aim at identifying genetic determinants and molecu-

lar effectors of glioma invasion by comparing, on one

hand, expression profiles of invasive vs. non-invasive

tumors and, on the other hand, expression patterns of

distinct areas within the same tumor.

Earlier data on genome-wide transcription analysis of

invasive compared to non-invasive gliomas have indi-

cated that tumor invasiveness is independent of a given

histologic or a molecular subset. Indeed, the signature

for invasiveness was associated with the differential

regulation of a discrete number of genes only. Among

those, we consistently found the gene for the mediator

of glioma invasion BEHAB/brevican, and also the genes

encoding transcription factors SOX2 and HEY1, suggest-

ing a possible role for these genes in glioma invasion.

Target genes for SOX2 and HEY1 encoding potential ef-

fectors of glioma invasion will be identified and tested

for their capacities of altering glioma cell motility.

Figure 3: Genotyping of tumor biopsies. Data obtained from real-time quantitative PCR (EGFR, CDKN2A, IL13RA2, ERBB2, NF1, PDGFRA, CKIT); loss of heterozygosity (PTEN, TP53, TRIM3); fluorescent in situ hybridization (1p/19q); pyrosequencing (IDH1/2) and sequencing of modified DNA (MGMT). ret = retention of both (polymorphic) alleles, loh = loss of heterozygosity (loss of one polymorphic allele), ni = non informative (no allelic polymorphism), nd = not done.



As a complementary approach, identification of invasion

genes also involves comparison of RNA levels between

the invasive glioma cells located at the periphery of the

tumor, and the non-invasive glioma cells embedded in

the tumor mass. Genes showing significant differential

expression between the distinct zones will be validated

for their abilities in modulating glioma invasion. Results

should provide clues on the molecular mechanisms of

glioma invasion and designate potential targets for cus-

tomized therapies to control glioma invasion.

In collaboration with Stephan Frank (Pathology, UHBS), Ist-

van Vajtai and Erik Vassella (University of Bern).

Some tumors, for which imaging data were available,

could be graded for their invasion capacities by mea-

surement of the thickness of the infiltration zone. Micro

RNAs are being extracted from formalin-fixed paraffin-

embedded tumors of known invasive properties, and

micro RNA expression compared by micro-array hybrid-

ization.

Positional information and tumor invasion

Mechanisms of migration and invasion are also stud-

ied using rat embryonic neural stem cells (NSCs). These

cells, when isolated from the embryonic cortex at E14.5

and put in culture in the presence of growth factors

such as FGF, undergo a change from dorsal to ventral

identity, as indicated by the expression of ventral genes

and the inhibition of the expression of dorsal genes.

After addition of bone morphogenic protein 4 (BMP4),

dorsal genes are re-expressed, ventral genes repressed.

Interestingly, NSCs also upregulate expression of sev-

Figure 4. Human cells dissociated from a grade IV GBM expand as GFAP/Nestin-positive adherent cells in FCS-containing medium, or as floating spheres in stem cell medium.



eral genes, such as SPARC, TNC and

HEY1, known to be expressed during

tumor invasion (Figure 6). Moreover,

these NSCs show migratory and inva-

sive properties in several in vitro as-

says. The identification of the molecu-

lar pathways involved in this transition

may help us to unravel the mecha-

nisms inducing invasion and migra-

tion of normal NSCs but hopefully also

of GBM tumor cells.

Luigi Mariani

Figure 5. confocal SOX2 immunolabeling in U373 glioma cells

Figure 6: Gene expression according to dorso-ventral positional information in NSCs exposed to FGF followed by BMP4 in vitro.Schematic coronal section of rat embryonic brain.



Survival, proliferation,deletion: ask the lymph node stroma!Transplantation and the immunoregulation game

From left to right: Maria Broggi, Nicolas Page, Simona Rossi Girard, Mathias Schmaler.



When we think about organ transplantation, the image

of patients first waiting for a transplant and then taking

medication for the rest of their life fills our imagination.

The surgical and the immunological knowledge of the

last 30 years have made it possible to live longer with an

appreciably better quality of life. The goal in transplan-

tation research is to be able to achieve graft tolerance

by convincing the transplanted body that the organ or

tissue received is not immunologically dangerous. How

to convince the host immune system that the danger

signals, the inflammation and the antigen that are flow-

ing in the body are harmless? This is a hard job...

To dampen a graft-specific immune response, we first

need to understand the starting point and how the en-

vironment modulates this immune response.

The players

More than 15 years ago a subset of T cells were described

bearing immunosuppressive properties and those cells

were called regulatory T cells (Tregs). Tregs are studied

with great interest because they are selectively able to

block the activation of T cells. The biggest problem for

in vivo treatment with Tregs is the high number of cells

needed to be transferred to achieve suppression of T cell

activation. Currently the clonal expansion is achieved in

culture and the cells are transferred into patients. Would

it be possible to boost the suppressive activity or the

number of Tregs directly in vivo? First we need to under-

stand where Tregs get activated and where they prefer-

entially exert their function. We take advantage of a skin

transplantation model where the host mouse is empty

of T and B cells and the skin donor harbours a mutation

in the gene encoding the MHC class II molecules. We can

modulate the outcome of transplantation by an adop-

tive co-transfer of alloreactive T cells (Teff) and Tregs

(Fig. 1a-model, b-graft survival). The first observation is

that the co-transferred Teff and Tregs reach and stay in

the lymph node (Ln). When Teff are transferred alone

in the host, they start to migrate in the grafted skin 9

days post-transfer leading to the skin-graft rejection.

Since, in presence of Tregs, Teff stay in the Ln and their

number only moderately increase, we concentrated our

effort to understand what is happening in the Ln. The

Ln is composed by several stroma cell subpopulations,

mainly categorised in 4 groups following the surface ex-

pression of a glycoprotein responsible for the sticking

of chemokines, called podoplanin or gp38 and CD31,

also known as platelet endothelial cell adhesion mol-

ecule (PECAM-1) (Fig. 2, adapted from Turley SJ et Al. ,

Nat Rev Immunol, 2010). Vascular endothelial cells ex-

press CD31 (lymph: CD31+gp38+, blood: CD31+gp38-).

The other cells, expressing only gp38 are known as fi-

broblastic reticular cells (FRC) and the cells negative

for both markers (DN) were recently described to be

pericytes-like-cells surrounding lymph and blood ves-

sels. The stromal compartment provides the structure

of the Ln and attracts and guides T cells and dendritic

cells (DC) to favour their contact. Furthermore, the stro-

ma cells of the Ln are producers of survival-, growth-

factors, cytokines and chemokines that influence both

T cells and DC. The recent knowledge on the active role

Fig. 1a) Skin transplantation model.b) Graft tolerance is dependent from the number of Tregs (10:1 means 10 Tregs per 1 Teff). Teff and Treg were adoptively transferred into the host twenty days after skin transplantation (day 0).



of stromal cells in modulating the immune response,

lead us to the idea that the environment where T cells

get activated or inhibited by the presence of Tregs, can

be conditioned to produce or abrogate the expression

of survival factors and growth factor influencing the im-

mune response.

The game

Transplanting a piece of tail skin expressing MHC class

II molecules with a mismatch onto a recipient mouse is

sufficient to induce an alloimmune response. Since our

recipient mouse is Rag ko, a strain defined by the ab-

sence of T or B cells, we transfer different ratio of Tregs

and Teff. Teff are monoclonal TcR transgenic cells that

recognise and get activated by the MHC class II alloanti-

gen expressed by the graft. Teff alloactivation, but not

proliferation, is impaired by the presence of Tregs (Fig.

3a). To achieve tolerance we observed that the number

of players in the lymph node field is determining the

outcome: if more Tregs are in the lymph node then Teff

(ratio > 1), a week after adoptive transfer, long term tol-

erance is achieved (Fig. 3b).

The field

T cells activation occurs in the Ln, where we can detect

migration of donor Langerhans-DC expressing allo-

MHC class II molecules. Our main research question is:

are Tregs supported in their regulatory function by the

Ln environment? The characterisation of this potential

function of the Ln stroma can lead to the design of new

therapeutic strategy that could modulate the suppres-

sive capacity of Tregs.

First we wondered whether stromal cells can respond

to activated T cells and if this is modulated by the pres-

ence of Tregs. Therefore, we isolated Ln stromal cells

through enzymatic digestion and isolated them by

cell sorting according to the expression of gp38 and

CD31 (Fig 4a). Our group (not published) and others 1,2

showed that stroma cells are able to respond to IFN-γ

produced by activated T cells by inducing the produc-

tion of Nitric Oxide (NO) and, in turn, by inhibiting T cell

Fig. 2 Stromal cell populations and their location in the Ln. (Adapted from: Turley SJ, et Al., Nat Rev Immunol, 2010) Fibroblastic reticular cell (FRC) networks are found in T cell zones in the paracortex of the lymph node, where T cells and dendritic cells (DCs) encounter each other. Follicular dendritic cell (FDC) networks organise B cell follicles. Lymphatic endothelial cells form the affer-ent and efferent lymphatic vessels; they mediate the movement of leukocytes and lymph into the lymph nodes. Blood endo-thelial cells line blood vessels and form specialised structures known as high endo-thelial venules (HEVs), which are surrounded by a thick basal lamina and perivascular sheath.

Fig. 3a) Tregs do not stop, but delay proliferation of Teff upon antigen recognition (right panel). Also Tregs undergo proliferation (left panel).b) The ratio between Tregs and Teff in the lymph node deter-mines the transplant outcome. A ratio above 1 predicts toler-ance.



proliferation in vitro (Fig. 4b). IL7 production by stromal

cells was upregulated as was RANKL, PDL1, MHC class II

and CD86 (Fig. 4c), suggesting that the stroma might

help the activation of T cells and control their activa-

tion status. In the presence of Tregs early in activation

nothing happens. It seems that the message the stroma

should get to be activated is missing. Indeed with high

Treg numbers the IFN-γ in the lymph node is strongly

reduced during activation. However, once tolerance is

established, Tregs themselves start to transcribe IFN-γ.

At the same time we detected an increased transcrip-

tion of RANKL, PDL1, MHC class II and CD86 by stromal

cells. The question that we currently aim to answer is

whether the same factors can elicit different effects de-

pending on the activation of T cells. A good candidate

molecule produced by Ln stromal cells that could play

an important role in helping Tregs survival and suppres-

sion is IL7 and the opportunity to collaborate with the

group of Daniela Finke provides us with several tools to

better define this potential mechanism. Indeed, during

tolerance establishment in vivo, we observe a X-expres-

sion pattern of IL-7, suggesting a pleiotropic role of this

cytokine depending on the presence of Tregs (Fig. 5a).

To assess the effect of IL-7 on the suppressive capac-

ity of Tregs we performed a suppression assay with or

without mrIL-7 in which Teff were activated with anti-

CD3/CD28 beads. In fact, we observed that the pres-

ence of mrIL-7 can substitute the presence of stromal

cells in sustaining the suppressive capacity of Tregs

(Fig. 5b). Furthermore, IL-7-conditioned Tregs showed

an increased suppressive activity in co-culture with allo-

activated Teff (Fig. 5c). The ongoing experiments in vivo

will clarify the role of IL-7 in a more complex system.

IL-7 is already being used in a clinical trial for bone mar-

row transplantation and correlations coming from pa-

tient data indicate that the Tregs pool can profit from

this treatment. Can we convince the stroma to better

sustain Tregs function? This is the challenge ahead of

us and the main workers on this project are Maria and

Mathias.

Other game, same players: outcome?

Transplantation of mismatch tissues or organs induc-

es a sterile inflammation and the direct activation of T

cells. What about inflammation induced by infection?

Mathias is investigating the activation pattern of lymph

node stroma cells during bacterial infections. Stroma

cells express the TLR receptor family and therefore have

the ability to respond to bacterial and danger pattern

molecules (PAMPs). Indeed, stimulation with different

PAMPs or TLR triggering molecules showed an activation

pattern of the lymph node stroma, but the effect is not

as dramatic as with IFN-γ stimulation. Usually, during

bacterial infection, pro-inflammatory cytokines are re-

leased at the site of infection and, together with PAMPs,

reach the Ln. The combination of cytokines and PAMPs

Fig. 4a) Magnetic cell sorting strategy to isolate stroma cells. FRC are Gp38+CD31- and the DN population is negative for both markers.b) Stroma is able to inhibit the proliferation of DC-activated T cells. T cells were cultured with stroma only, stroma and DC 1:1 or only with DC and the proliferation was assessed after 7 days co-culture.

12 WISSENSCHAFT | SCIENCE INSTITUTE OF PHYSIOLOGY



increases the expression of ICAM, VCAM, cytokines and

chemokines on the surface of stroma cells in the lymph

nodes involving increased T cells recruitment. What is

the role of stroma during infection? Sustaining T cell ac-

tivation? Maintaining a structural integrity of the lymph

node or helping Tregs dampen the cytokine storm? This

research field is just at the beginning and we hope to

soon better understand the role of the different players.

Recently another group described the ability of lymph

node stroma cells to clonally delete OT-I CD8 T cells in

the context of the iFABP-tOVA model, where FRC were

shown to be able to process ovalbumin and display OTI

peptide on MHC class I molecules. Stroma cells delete in

the periphery the autoreactive OVA cells3. A similar sys-

tem for the CD4 T cells was never described.

During the evaluation of the ability of lymph node stro-

ma cells to respond to TLR triggering, Nicolas observed

in vivo and in vitro that TLR9 activation by immunostim-

ulatory CpG oligodeoxynucleotides induced high level

of MHC class II molecules at the surface of the lymph

node stroma cells. In autoimmune diseases such as

Systemic Lupus Erythematosous a defective clearance

of dead and dying cells are known to contribute to its

ethiopathogenesis. This defective clearance of apoptot-

ic cells results in accumulation of apoptotic debris and

necrotic DNA. Together with autoantibodies, necrotic

DNA form DNA-containing immune complexes that will

activate TLR9 signaling in dendritic cells. This excessive

TLR9 activation drives production of IFN-γ, leading to

Fig. 5a) IL-7 transcription is downregulated over time in lymph node stroma of mice trans-planted and adoptively transferred with Teff (squares) and is upregulated over time in mice transplanted and adoptively transferred with Tregs:Teff at a ratio of 10:1 (circles).b) Addition of IL-7 in co-culture can substitute the effect of stroma on ABM proliferation. Co-cultured performed for 3 days. T cells were activated with anti-CD3/28 beads and cultured in presence or absence of Ln stroma or 50 ng/ml rmIL-7. c) IL-7 improves Tregs suppressive function in vitro. Proliferation of ABM cells in co-culture for 5 days with allogenic DC in presence or absence of Tregs.

an alteration of T and B-cell profiles, disruption of Treg

networks, and exacerbates the clinical manifestation of

lupus. In a lupus-prone mouse MRL/lpr, MHC class II ex-

pression is increased at the surface of Ln FRC (our own

observation) and we are currently evaluating the cellu-

lar and molecular basis of this TLR9-mediated MHC class

II expression in Ln stroma cells and its biological impact.

We are especially interested in investigating the poten-

tial of Ln stroma cells to maintain peripheral tolerance

by controlling the pool of autoreactive CD4+ lympho-

cytes in a model of lupus.

Taken all together lymph node stroma cells are efficient

players of the immunoregulation game. They can react

to cytokines and microbial stimuli to sustain or down

modulate the immune response. A better understand-

ing of this cellular compartment will open new “regula-

tory” perspectives.

Acknowledgement

The Immunoregulation group would like to thank the

sorting-facility for the incredible work performed with

us, the animal care facility for their help and all the

groups at the DBM that help us to “win” the game.

Simona Rossi Girard

INSTITUTE OF PHYSIOLOGY WISSENSCHAFT | SCIENCE 13


DEPARTMENT OF BIOMEDICINE AUSZEICHNUNGEN | CONGRATUL ATIONS 13

Literature

1. Lukacs-Kornek, V. et al. Regulated release of nitric oxide by nonhematopoietic stroma controls expan-

sion of the activated T cell pool in lymph nodes. Nat Immunol (2011).doi:10.1038/ni.2112

2. Siegert, S. et al. Fibroblastic Reticular Cells From Lymph Nodes Attenuate T Cell Expansion by Produc-ing Nitric Oxide. PLoS ONE 6, e27618 (2011).

Markus Heim von der Forschungsgruppe Hepatology

(DBM Hebelstrasse) hat am 24. April 2012 gemeinsam

mit Lars French den mit 200‘000 CHF dotierten Otto

Naegeli Preis erhalten. Damit wurden zwei Experten

ausgezeichnet, die mit ihrer translationalen biomedi-

zinischen Forschung Grundlagen- und klinische For-

schung miteinander verknüpfen. Markus Heim wurde

für seine international anerkannte Forschung über die

Otto Naegeli Preis 2012 an Markus Heim

molekularen Mechanismen der Wechselwirkung zwi-

schen dem Hepatitis C Virus und der Interferon-Signal-

gebung in der Leber geehrt. Er konnte mit seinem Team

nachweisen, warum gängige Therapieansätze oft nicht

den gewünschten Effekt erzielten. Der Otto Naegeli

Preis wird alle zwei Jahre an herausragende Persönlich-

keiten auf dem Gebiet der medizinischen Forschung

verliehen.

3. Fletcher, A. L. et al. Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. Journal of Experimental Medicine 207, 689-697 (2010)

Von links nach rechts: Markus Heim, H.J. Schürmann, Lars French. Foto: Vijay Shanker

«Gute und sauböse Zelle»:Ed Palmer gewinnt Science Slam 2012

14 AUSZEICHNUNGEN | CONGRATUL ATIONS DEPARTMENT OF BIOMEDICINE


Ed Palmer von der Forschungsgruppe

Transplantation Immunology (DBM He-

belstrasse) hat mit seiner Präsentation

« Wäg mit de böse Immunzälle: E vier-

sekündigs Tächtelmächtel und die Sach

isch gritzt ! » den von der Universität

Basel und der Fachhochschule Nord-

westschweiz getragenen Science Slam

gewonnen. In dem Wettbewerb treten

acht Wissenschaftler gegeneinander an

und stellen in acht Minuten ihre For-

schung auf unkonventionelle Weise vor.

Wer diesen genialen Vortrag am 27. April

2012 verpasst hat, kann ihn auf dem

Youtube-Kanal der Universität Basel

nochmals anschauen. So unterhaltsam

kann Wissenschaft ein!

Kläbeane

Körpermolekül

MolekularsTächtelmächtel

➜

BiochemischesFüürwerk

➜

WÄG mit dr Böse T Zälle➜

Zämmefassig

….und 100 Milliarde mool wiiderhole !!!

Das brucht 4 sekunde

DissertationenMit der Doktorprüfung am 5. März 2012 schloss Marco

Osterwalder von der Forschungsgruppe Developmen-

tal Genetics (Departement Biomedizin Mattenstrasse)

erfolgreich seine Dissertationszeit ab. Das Thema sei-

ner Doktorarbeit lautete: «Genome-wide identification

of Hand2 target regions in mouse embryos using dRM-

CE, a new genetic tool».

Am 29. März 2012 stellte sich Michael Dill von der For-

schungsgruppe Hepatology (Departement Biomedizin

Hebelstrasse) dem Dissertationskomitee. Der Titel sei-

ner Dissertation lautete: «Hepatitis C: Host-virus inter-

actions and their impact on treatment of response».

Venia docendi anMarianne Böni-Schnetzler

In ihrer Sitzung am 11. April 2012 erteilte die Regenz

der Universität Basel Marianne Böni-Schnetzler von der

Forschungsgruppe Diabetes Research (Departement

Biomedizin Hebelstrasse) die Venia docendi für Endo-

krinologie, Diabetologie und Metabolismus.

Herzliche Gratulation an alle!

DEPARTMENT OF BIOMEDICINE PUBLICATIONS 15


Selected publications by DBM members

Below you can find the abstracts of recent articles published by members of the DBM. The abstracts are grouped according to the impact factor of the journal where the work appeared. To be included, the papers must meet the following criteria:

1. The first author, last author or corresponding author (at least one of them) is a member of the DBM. 2. The DBM affiliation must be mentioned in the authors list as it appeared in the journal. 3. The final version of the article must be available (online pre-publications will be included when the correct volume, page numbers etc. becomes available).

We are primarily concentrating on original articles. Due to page constraints, abstracts of publications that appeared in lower ranked journals may not be able to be included. Review articles are generally not considered, unless they appeared in the very top journals (e.g. Cell, Science, Nature, NEJM, etc.). The final decision concerning inclusion of an abstract will be made by the chair of the Department of Biomedicine.

If you wish that your article will appear in the next issue of DBM Facts please submit a pdf file to the Departmental Assistant, Manuela Bernasconi: [email protected]

Deadline for the next issue is July 31, 2012.

Nature Immunology Vol. 13 No. 5 May 2012 IF25,6

Peroxisome-derived lipids are self antigens that stimulate invariant natural killer T cells in the thymus

Federica Facciotti1,5, Gundimeda S Ramanjaneyulu1, Marco Lepore1, Sebastiano Sansano1, Marco Cavallari1,Magdalena Kistowska1,5, Sonja Forss-Petter2, Guanghui Ni3, Alessia Colone4, Amit Singhal4, Johannes Berger2,Chengfeng Xia3, Lucia Mori1,4, & Gennaro De Libero1,4

1 Experimental Immunology, Department of Biomedicine, University Hospital Basel, Switzerland2 Medical University of Vienna, Center for Brain Research, Vienna, Austria.3 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute

of Botany, Chinese Academy of Sciences, Kunming, China.4 Singapore Immunology Network, Agency for Science, Technology and Research, Biopolis, Singapore.5 Istituto Nazionale di Genetica Molecolare, Milano, Italy (F.F.), and Department of Dermatology,

Zurich University Hospital, Switzerland (M.K.).

The development and maturation of semi-invariant natural killer T cells

(i NKT cells) rely on the recognition of self antigens presented by CD1d

restriction molecules in thymus. The nature of the stimulatory thymic

self lipids remains elusive. We isolated lipids from thymocytes and found

that ether-bonded mono-alkyl glycerophosphates and the precursors

and degradation products of plasmalogens stimulated i NKT cells. Syn-

thetic analogs showed high potency in activating thymic and peripheral

i NKT cells. Mice deficient in the peroxisomal enzyme glyceronephos-

phate O-acyltransferase (GNPAT), essential for the synthesis of ether lip-

ids, had significant alteration of the thymic maturation of i NKT cells and

fewer i NKT cells in both thymus and peripheral organs, which confirmed

the role of ether-bonded lipids as i NKT cell antigens. Thus, peroxisome-

derived lipids are nonredundant self antigens required for the generation

of a full i NKT cell repertoire.

16 PUBLICATIONS DEPARTEMENT BIOMEDIZIN


Developmental Cell 22, 837–848, April 17, 2012 IF13,9

GLI3 Constrains Digit Number by Controlling Both Progenitor Proliferation and BMP-Dependent Exit to Chondrogenesis

Javier Lopez-Rios1, Dario Speziale1,*, Dimitri Robay1,5,*, Martina Scotti3,*, Marco Osterwalder1, Gretel Nusspaumer2,Antonella Galli1,6, Georg A. Holländer2,4, Marie Kmita3 and Rolf Zeller1

Summary

Inactivation of Gli3, a key component of Hedgehog signaling in verte-

brates, results in formation of additional digits (polydactyly) during limb

bud development. The analysis of mouse embryos constitutively lacking

Gli3 has revealed the essential GLI3 functions in specifying the anteropos-

terior (AP) limb axis and digit identities. We conditionally inactivated Gli3

during mouse hand plate development, which uncoupled the resulting

preaxial polydactyly from known GLI3 functions in establishing AP and

digit identities. Our analysis revealed that GLI3 directly restricts the ex-

pression of regulators of the G1–S cell-cycle transition such as Cdk6 and

1 Developmental Genetics, Department of Biomedicine2 Department of Biomedicine and Children’s Hospital University of Basel, Switzerland3 Laboratory of Genetics and Development, Institut de Recherches Cliniques de Montréal, Québec H2W1R7, Canada4 Developmental Immunology, Department of Pediatrics, University of Oxford, UK5 Basilea Pharmaceutica International, Basel, Switzerland6 Department of Medicine and Genetics&Development, Herbert Irving Comprehensive Cancer

Center, Columbia University Medical Center, New York, USA* These authors contributed equally to this work

Gastroenterology 2012; 142: 967–977 IF 12,0

Disruption of Notch1 Induces Vascular Remodeling, IntussusceptiveAngiogenesis, and Angiosarcomas in Livers of Mice

Michael T. Dill1, Sonja Rothweiler1, Valentin Djonov2, Ruslan Hlushchuk2, Luigi Tornillo3, Luigi Terracciano3, Silvia Meili-Butz1, Freddy Radtke5, Markus H. Heim1,4, David Semela1,4

Background & Aims: Notch signaling mediates embryonic vascular de-

velopment and normal vascular remodeling; Notch1 knockout mice de-

velop nodular regenerative hyperplasia (NRH). The pathogenesis of NRH

is unclear, but has been associated with vascular injury in the liver sinu-

soids in clinical studies. We investigated the role of Notch1 signaling in

liver sinusoidal endothelial cells (LSECs).

Methods: We studied MxCre Notch1lox/lox mice (conditional knockout mice

without tissue-specific disruption of Notch1); mice with hepatocyte-spe-

cific knockout were created by crossing Notch1lox/lox with Alb-Cre+/¯ mice.

Portal vein pressure was measured; morphology of the hepatic vascula-

ture was assessed by histologic and scanning electron microscopy analy-

ses. We performed functional and expression analyses of isolated liver

cells.

Results: MxCre-induced knockout of Notch1 led to NRH, in the absence of

fibrosis, with a persistent increase in proliferation of LSECs. Notch1 dele-

tion led to de-differentiation, vascular remodeling of the hepatic sinusoi-

dal microvasculature, intussusceptive angiogenesis, and dysregulation

1 Department of Biomedicine, University Basel, Switzerland2 Institute of Anatomy, University Berne, Switzerland3 Institute of Pathology4 Division of Gastroenterology and Hepatology, University Hospital Basel, Switzerland;5 Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research, Epalinges, Switzerland

of ephrinB2/EphB4 and endothelial tyrosine kinase. Time-course experi-

ments revealed that vascular changes preceded node transformation.

MxCre Notch1lox/lox mice had reduced endothelial fenestrae and developed

portal hypertension and hepatic angiosarcoma over time. In contrast,

mice with hepatocyte-specific disruption of Notch1 had a normal pheno-

type.

Conclusions: Notch1 signaling is required for vascular homeostasis of

hepatic sinusoids; it maintains quiescence and differentiation of LSECs in

adult mice. Disruption of Notch1 signaling in LSECs leads to spontaneous

formation of angiosarcoma, indicating its role as a tumor suppressor in

the liver endothelium.

Developmental Cell

Article

GLI3 Constrains Digit Numberby Controlling Both Progenitor Proliferationand BMP-Dependent Exit to ChondrogenesisJavier Lopez-Rios, 1 Dario Speziale, 1,5 Dimitri Robay, 1,5,6 Martina Scotti, 3,5 Marco Osterwalder, 1 Gretel Nusspaumer, 2

Antonella Galli, 1,7 Georg A. Holla ¨nder, 2,4 Marie Kmita, 3 and Rolf Zeller 1,*1Developmental Genetics, Department of Biomedicine2Department of Biomedicine and Children’s HospitalUniversity of Basel, 4058 Basel, Switzerland3Laboratory of Genetics and Development, Institut de Recherches Cliniques de Montre ´al, Montre al, Que bec H2W1R7, Canada4Developmental Immunology, Department of Pediatrics, University of Oxford, Oxford OX3 9DU, UK5These authors contributed equally to this work6Present address: Basilea Pharmaceutica International, 4005 Basel, Switzerland7Present address: Department of Medicine and Genetics & Development, Herbert Irving Comprehensive Cancer Center,Columbia University Medical Center, New York, NY 10032, USA*Correspondence: [email protected] 10.1016/j.devcel.2012.01.006

SUMMARY

Inactivation of Gli3 , a key component of Hedgehogsignaling in vertebrates, results in formation of addi-tional digits (polydactyly) during limb bud develop-ment. The analysis of mouse embryos constitutivelylacking Gli3 has revealed the essential GLI3 functionsin specifying the anteroposterior (AP) limb axis anddigit identities. We conditionally inactivated Gli3during mouse hand plate development, which un-coupled the resulting preaxial polydactyly fromknown GLI3 functions in establishing AP and digitidentities. Our analysis revealed that GLI3 directlyrestricts the expression of regulators of the G 1–Scell-cycle transition such as Cdk6 and constrains Sphase entry of digit progenitors in the anterior handplate. Furthermore, GLI3 promotes the exit ofproliferating progenitors toward BMP-dependentchondrogenic di�erentiation by spatiotemporallyrestricting and terminating the expression of theBMP antagonist Gremlin1 . Thus, Gli3 is a negativeregulator of the proliferative expansion of digit pro-genitors and acts as a gatekeeper for the exit tochondrogenic di�erentiation.

INTRODUCTION

Hedgehog signaling is a major regulator of organogenesis inboth vertebrate and invertebrate embryos ( Jiang and Hui,2008; Varjosalo et al., 2006 ). Analysis of Sonic Hedgehog(SHH) signaling has provided insights into how SHH orchestratesvertebrate limb bud development ( Chiang et al., 2001; Harfeet al., 2004; Riddle et al., 1993; Zeller et al., 2009 ). In the posteriormesenchyme, SHH is produced by the polarizing region (ZPA) to

control anteroposterior (AP) axis specification and proliferativeexpansion of mesenchymal progenitors together with FGF andWnt signals ( ten Berge et al., 2008; Towers et al., 2008; Zhuet al., 2008 ). All three types of signals stimulate the expressionofMycn , which appears to be a key regulator o� imb budmesen-chymal cell proliferation because its inactivation decreasesproliferation, resulting in smaller limb skeletal elements andsyndactyly ( Ota et al., 2007 ).SHH is part of a self-regulatory system that interlinks the ZPA

with the apical ectodermal ridge (AER) and controls limb budoutgrowth by coordinating BMP, FGF, and SHH signaling withthe clearance of retinoic acid from the distal mesenchyme(Probst et al., 2011; Zeller et al., 2009 ). A key node in this systemis the BMP antagonist Gremlin1 (GREM1), which keeps BMPactivity low during limb bud outgrowth ( Be nazet et al., 2009 ).This feedback signaling system is self-terminating, as (1) the ex-panding population of Shh descendants is refractory to Grem1expression ( Scherz et al., 2004 ), and (2) high AER-FGF signalinginhibits Grem1 expression in the distal mesenchyme ( Verheydenand Sun, 2008 ). AER-FGF signaling increases during limb budoutgrowth, which eventually inhibits Grem1 expression. Thistermination of Grem1 expression results in a renewed raise ofBMP activity ( Be nazet et al., 2009; Verheyden and Sun, 2008 ),which initiates condensation and chondrogenic di�erentiationof mesenchymal progenitors ( Bandyopadhyay et al., 2006; Piz-ette and Niswander, 2000 ). In digit primordia, di�erential BMPsignal transduction in the distal phalanx-forming region is likelyrequired to determine the definitive identities ( Suzuki et al.,2008; Witte et al., 2010 ).In vertebrates, the expression of SHH target genes is

regulated by the GLI1-3 transcription factors. In particular,SHH signal transduction at the primary cilia inhibits the proteo-lytic processing of GLI3 to a transcriptional repressor (GLI3R;Wen et al., 2010 ). This results in accumulation of GLI1-3 activa-tors in the posterior limb bud, whereas GLI3R is the predominantGLI isoform in the anterior mesenchyme ( Ahn and Joyner, 2004;Wang et al., 2000 ). A genome-wide screen for cis- regulatory

Developmental Cell 22 , 837–848, April 17, 2012 ª 2012 Elsevier Inc. 837

constrains S phase entry of digit progenitors in the anterior hand plate.

Furthermore, GLI3 promotes the exit of proliferating progenitors to-

ward BMP-dependent chondrogenic differentiation by spatiotemporally

restricting and terminating the expression of the BMP antagonist Grem-

lin1. Thus, Gli3 is a negative regulator of the proliferative expansion of

digit progenitors and acts as a gatekeeper for the exit to chondrogenic

differentiation.



PNAS cgi/doi/10.1073/pnas.1108718109 IF 9,7

Protooncogene Ski cooperates with the chromatin-remodeling factor Satb2 in specifying callosal neurons

First insights into the molecular programs orchestrating the progression

from neural stem cells to cortical projection neurons are emerging. Loss

of the transcriptional regulator Ski has been linked to the human 1p36

deletion syndrome, which includes central nervous system defects. Here,

we report critical roles for Ski in the maintenance of the neural stem cell

pool and the specification of callosal neurons. Ski-deficient callosal neu-

rons lose their identity and ectopically express the transcription factor

Ctip2. The misspecified callosal neurons largely fail to form the corpus

callosum and instead redirect their axons toward subcortical targets. We

1 Institute of Physiology, Department of Biomedicine, University of Basel, Switzerland2 Institute of Cell Biology and Neurobiology, Neurocure Cluster of Excellence, Charité-Universitätsmedizin Berlin, Campus Mitte, Germany3 Institute of Anatomy and Cell Biology, Albert-Ludwigs-University Freiburg, Germany4 Biozentrum, University of Basel, Switzerland5 Department of Cancer Biology, Lerner Research Institute, Cleveland, OH 44195

identify the chromatin-remodeling factor Satb2 as a partner of Ski, and

show that both proteins are required for transcriptional repression of

Ctip2 in callosal neurons. We propose a model in which Satb2 recruits Ski

to the Ctip2 locus, and Ski attracts histone deacetylases, thereby enabling

the formation of a functional nucleosome remodeling and deacetylase

repressor complex. Our findings establish a central role for Ski–Satb2

interactions in regulating transcriptional mechanisms of callosal neuron

specification.

Constanze Baranek1, Manuela Dittrich1, Srinivas Parthasarathy2, Carine Gaiser Bonnon1,3, Olga Britanova2, Dmitriy Lanshakov2, Fatiha Boukhtouche4, Julia E. Sommer4, Clemencia Colmenares5, Victor Tarabykin2, Suzana Atanasoski1,3

European Cells and Materials Vol. 23 2012 (pages 222-236) IF 9,6

Influence of in vitro maturation of engineered cartilage on the outcome of osteochondral repair in a goat model

S. Miot1, W. Brehm2,5, S. Dickinson3, T. Sims3, A. Wixmerten1, C. Longinotti4, A.P. Hollander3, P. Mainil-Varlet2, I. Martin1

AbstractThis study was designed to determine if the maturation stage of engi-

neered cartilage implanted in a goat model of cartilage injury influences

the repair outcome. Goat engineered cartilage was generated from au-

tologous chondrocytes cultured in hyaluronic acid scaffolds using 2 d, 2

weeks or 6 weeks of pre-culture and implanted above hydroxyapatite/hy-

aluronic acid sponges into osteochondral defects. Control defects were

left untreated or treated with cell-free scaffolds. The quality of repair tis-

sues was assessed 8 weeks or 8 months post implantation by histological

staining, modified O’Driscoll scoring and biochemical analyses. Increasing

pre-culture time resulted in progressive maturation of the grafts in vitro.

After 8 weeks in vivo, the quality of the repair was not improved by any

treatment. After 8 months, O’Driscoll histology scores indicated poor car-

1 Departments of Surgery and Biomedicine, University Hospital Basel, Switzerland2 Osteoarticular Research Group, Institute of Pathology, University of Bern, Switzerland3 School of Cellular & Molecular Medicine, University of Bristol, UK4 Fidia Advanced Biopolymers (FAB), Abano Terme, Italy5 Surgical Veterinary Clinics, University of Leipzig, Germany

tilage architecture for untreated (29.7 ± 1.6) and cell-free treated groups

(24.3 ± 5.8). The histology score was improved when cellular grafts were

implanted, with best scores observed for grafts pre-cultured for 2 weeks

(16.3 ± 5.8). As compared to shorter pre-culture times, grafts cultured for

6 weeks (histology score: 22.3 ± 6.4) displayed highest type II/I collagen

ratios but also inferior architecture of the surface and within the defect,

as well as lower integration with native cartilage. Thus, pre-culture of en-

gineered cartilage for 2 weeks achieved a suitable compromise between

tissue maturity and structural/integrative properties of the repair tissue.

The data demonstrate that the stage of development of engineered car-

tilage is an important parameter to be considered in designing cartilage

repair strategies.



Biomaterials 33 (2012) 5085–5093 IF 7,8

Enhancing the biological performance of synthetic polymeric materials by decoration with engineered, decellularized extracellular matrix Nasser Sadr1,2,3, Benjamin E. Pippenger1,2, Arnaud Scherberich1,2, David Wendt1,2, Sara Mantero3, Ivan Martin1,2,Adam Papadimitropoulos1,2

AbstractMaterials based on synthetic polymers can be extensively tailored in their

physical properties but often suffer from limited biological functional-

ity. Here we tested the hypothesis that the biological performance of

3D synthetic polymer-based scaffolds can be enhanced by extracellular

matrix (ECM) deposited by cells in vitro and subsequently decellularized.

The hypothesis was tested in the context of bone graft substitutes, using

polyesterurethane (PEU) foams and mineralized ECM laid by human mes-

enchymal stromal cells (hMSC). A perfusion-based bioreactor system was

critically employed to uniformly seed and culture hMSC in the scaffolds

and to efficiently decellularize (94% DNA reduction) the resulting ECM

while preserving its main organic and inorganic components. As com-

1 Department of Surgery, University Hospital Basel, Switzerland2 Department of Biomedicine, University Hospital Basel, Switzerland3 Bioengineering Department, Politecnico di Milano,Milan, Italy

pared to plain PEU, the decellularized ECM-polymer hybrids supported

the osteoblastic differentiation of newly seeded hMSC by upregulating

the mRNA expression of typical osteoblastic genes (6-fold higher bone

sialoprotein; 4-fold higher osteocalcin and osteopontin) and increasing

calcium deposition (6-fold higher), approaching the performance of ce-

ramic-based materials. After ectopic implantation in nude mice, the de-

cellularized hybrids induced the formation of a mineralized matrix posi-

tively immunostained for bone sialoprotein and resembling an immature

osteoid tissue. Our findings consolidate the perspective of bioreactor-

based production of ECM-decorated polymeric scaffolds as off-the-shelf

materials combining tunable physical properties with the physiological

presentation of instructive biological signals.

The Journal of Neuroscience April 18, 2012, 32(16):5654 –5666 IF 7,2

Neurogenic Subventricular Zone Stem/Progenitor Cells Are Notch1-Dependent in Their Active But Not Quiescent State

Onur Basak1,*, Claudio Giachino1,2,*, Emma Fiorini3, H. Robson MacDonald3, and Verdon Taylor1,2

The adult mammalian forebrain contains neural stem/progenitor cells

(NSCs) that generate neurons throughout life. As in other somatic stem

cell systems, NSCs are proposed to be predominantly quiescent and pro-

liferate only sporadically to produce more committed progeny. However,

quiescence has recently been shown not to be an essential criterion for

stem cells. It is not known whether NSCs show differences in molecular

dependence based on their proliferation state. The subventricular zone

(SVZ) of the adult mouse brain has a remarkable capacity for repair by

activation of NSCs. The molecular interplay controlling adult NSCs dur-

ing neurogenesis or regeneration is not clear but resolving these interac-

tions is critical in order tounderstand brainhomeostasisandrepair. Using

conditional genetics and fate mapping, we show that Notch signaling is

essential for neurogenesis in the SVZ. By mosaic analysis, we uncovered

1 Department of Molecular Embryology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany2 Embryology and Stem Cell Biology, Department of Biomedicine, University of Basel, Switzerland3 Ludwig Center for Cancer Research, University of Lausanne, Epalinges, Switzerland* These authors contributed equally to this work

a surprising difference in Notch dependence between active neurogenic

and regenerative NSCs. While bothactive and regenerative NSCs depend

upon canonical Notch signaling, Notch1-deletion results in a selective loss

of active NSCs (aNSCs). In sharp contrast, quiescent NSCs (qNSCs) remain

after Notch1 ablation until induced during regeneration or aging, where-

upon they become Notch1-dependent and fail to fully reinstate neuro-

genesis. Our results suggest that Notch1 is a key component of the adult

SVZ niche, promoting maintenance of aNSCs, and that this function is

compensated in qNSCs. Therefore, we confirm the importance of Notch

signaling for maintaining NSCs and neurogenesis in the adult SVZ and

reveal that NSCs display a selective reliance on Notch1 that may be

dictated by mitotic state.



Cardiovascular Research (2012) 93, 454–462 IF 6,0

NOX2-derived reactive oxygen species are crucial for CD29-inducedpro-survival signalling in cardiomyocytes

Berit I. Rosc-Schlüter1, Stéphanie P. Häuselmann1, Vera Lorenz1, Michika Mochizuki1, Federica Facciotti2, Otmar Pfister1,3,Gabriela M. Kuster1,3

AimsThe highly expressed cell adhesion receptor CD29 (b1-integrin) is es-

sential for cardiomyocyte growth and survival, and its loss of function

causes severe heart disease. However, CD29-induced signalling in cardio-

myocytes is ill defined and may involve reactive oxygen species (ROS).

A decisive source of cardiac ROS is the abundant NADPH oxidase (NOX)

isoform NOX2. Because understanding of NOX-derived ROS in the heart

is still poor, we sought to test the role of ROS and NOX in CD29-induced

survival signalling in cardiomyocytes.

Methods and resultsIn neonatal rat ventricular myocytes, CD29 activation induced intracel-

lular ROS formation (oxidative burst) as assessed by flow cytometry

using the redox-sensitive fluorescent dye dichlorodihydrofluorescein di-

acetate. This burst was inhibited by apocynin and diphenylene iodonium.

Further, activation of CD29 enhanced NOX activity (lucigenin-enhanced

chemiluminescence) and activated the MEK/ERK and PI3K/Akt survival

pathways. CD29 also induced phosphorylation of the inhibitory Ser9 on

the pro-apoptotic kinase glycogen synthase kinase-3β in a PI3K/Akt- and

MEK-dependent manner, and improved cardiomyocyte viability under

conditions of oxidative stress. The ROS scavenger MnTMPyP or adenoviral

co-overexpression of the antioxidant enzymes superoxide dismutase and

catalase inhibited CD29-induced pro-survival signalling. Further, CD29-

induced protective pathways were lost in mouse cardiomyocytes defi-

cient for NOX2 or functional p47phox, a regulatory subunit of NOX.

Conclusionp47phox-dependent, NOX2-derived ROS are mandatory for CD29-induced

pro-survival signalling in cardiomyocytes. These findings go in line with

a growing body of evidence suggesting that ROS can be beneficial to the

cell and support a crucial role for NOX2-derived ROS in cell survival in the

heart.

1 Myocardial Research, Department of Biomedicine, University and University Hospital Basel, Switzerland2 Experimental Immunology, Department of Biomedicine, University and University Hospital

Basel, Switzerland3 Division of Cardiology, University Hospital Basel, Switzerland

Cardiovascular Research (2012) 93, 1–10 IF 6,0

T-cadherin attenuates insulin-dependent signalling, eNOS activation, and angiogenesis in vascular endothelial cells

AimsT-cadherin (T-cad) is a glycosylphosphatidylinositol-anchored cadherin

family member. Experimental, clinical, and genomic studies suggest a

role for T-cad in vascular disorders such as atherosclerosis and hyperten-

sion, which are associated with endothelial dysfunction and insulin resis-

tance (InsRes). In endothelial cells (EC), T-cad and insulin activate similar

signalling pathways [e.g. PI3-kinase (PI3K)/Akt/mammalian target of ra-

pamycin (mTOR)] and processes (e.g. angiogenesis). We hypothesize that

T-cad is a regulatory component of insulin signalling in EC and therefore a

determinant of the development of endothelial InsRes.

Methods and resultsWe investigated T-cad-dependent effects on insulin sensitivity using hu-

man EC stably transduced with respect to T-cad overexpression or T-cad

silencing. Responsiveness to insulin was examined at the level of effec-

tors of the insulin signalling cascade, EC nitric oxide synthase (eNOS)

activation, and angiogenic behaviour. Overexpression and ligation of

T-cad on EC attenuates insulin-dependent activation of the PI3K/Akt/

mTOR signalling axis, eNOS, EC migration, and angiogenesis. Conversely,

T-cad silencing enhances these actions of insulin. Attenuation of EC re-

sponsiveness to insulin results from T-cad-mediated chronic activation of

the Akt/mTOR-dependent negative feedback loop of the insulin cascade

and enhanced degradation of the insulin receptor (IR) substrate. Coim-

munoprecipitation experiments revealed an association between T-cad

and IR. Filipin abrogated inhibitory effects of T-cad on insulin signalling,

demonstrating localization of T-cad-insulin cross-talk to lipid raft plasma

membrane domains. Hyperinsulinaemia up-regulates T-cad mRNA and

protein levels in EC.

ConclusionT-cad expression modulates signalling and functional responses of EC to

insulin. We have identified a novel signalling mechanism regulating insu-

lin function in the endothelium and attribute a role for T-cad up-regula-

tion in the pathogenesis of endothelial InsRes.

1 Laboratory for Signal Transduction, Department of Biomedicine, Basel University Hospital, Switzerland

2 Division of Cardiology, Kantonsspital Luzern, Switzerland* These authors contributed equally to this work

Maria Philippova1,*, Manjunath B. Joshi1,*, Dennis Pfaff1, Emmanouil Kyriakakis1, Kseniya Maslova1, Paul Erne2,Thérèse J. Resink1,*



The Journal of Biological Chemistry Vol.287, Number 13, March 23, 2012 IF 5,3

Proteasomal Inhibition Restores Biological Function of Mis-sense MutatedDysferlin in Patient-derived Muscle Cells*

Bilal A. Azakir, Sabrina Di Fulvio, Jochen Kinter, and Michael Sinnreich1

Dysferlin is a transmembrane protein implicated in surfacemembrane re-

pair of muscle cells. Mutations in dysferlin causethe progressive muscular

dystrophies Miyoshi myopathy, limbgirdle muscular dystrophy 2B, and

distal anterior compartmentmyopathy. Dysferlinopathies are inherited

in an autosomalrecessive manner, and many patients with this disease

harbormis-sense mutations in at least one of their two pathogenicDYSF

alleles. These patients have significantly reduced or absent dysferlin lev-

elsin skeletal muscle, suggesting that dysferlin encoded by mis-sense

alleles is rapidly degraded by the cellular quality control system. We rea-

soned that mis-sensemutated dysferlin, if salvaged from degradation,

might be biologically functional. We used a dysferlin-deficient human

myoblast culture harboring the common R555W mis-sense alleleand a

DYSF-null allele, as well as control human myoblast cultures harboring ei-

ther two wild-type or two null alleles. We measured dysferlin protein and

mRNA levels,resealing kinetics of laser-induced plasmalemmal wounds,

myotube formation, and cellular viability after treatment of the human

myoblast cultures with the proteasome inhibitors lactacystin orbort-

ezomib (Velcade). We show that endogenous R555Wmis-sense mutated

dysferlin is degraded by the proteasomalsystem. Inhibition of the protea-

some by lactacystin or Velcade increases the levels of R555W mis-sense

mutated dysferlin. This salvaged protein is functional as it restores plas-

mamembrane resealing in patient-derived myoblasts and reverses their

deficit in myotube formation. Bortezomib and lactacystin did not cause

cellular toxicity at theregimen used.Our results raise the possibility that

inhibition of the degradation pathway of mis-sense mutated dysferlin

could be usedas a therapeutic strategy for patients harboring certain dys-

ferlin mis-sense mutations.

*This work was supported by Myosuisse, Association Française contre les Myopathies, Muscular Dystrophy Association Canada-Amyotrophic Lateral Sclerosis Society Canada-Canadian Institutes of Health Research (MDAC-ALS-CIHR) Partnership, and the Swiss National Science Foundation.

1 Neuromuscular Research Group, Departments of Neurology and Biomedicine, University Hospi-tal and University of Basel, Switzerland

European Respiratory Journal 2012; 39: 705–711 IF 5,9

Cigarette smoke inhibits lung fibroblast proliferation by translationalmechanisms

Abstract:Cigarette smoke is a major cause of chronic obstructive pulmonary dis-

ease (COPD) and emphysema. Although cigarette smoke represses cel-

lular proliferation, the molecular mechanisms underlying this phenom-

enon are unknown. CCAAT/enhancer-binding proteins (C/EBPs) are key

regulators of cell cycle progression, differentiation and pro-inflammatory

gene expression, are regulated predominantly at the translational level

and may be involved in the pathogenesis of COPD. The aim of this study

was to assess the effect of cigarette smoke on proliferation and the ex-

pression and translational regulation of C/EBPα and C/EBPβ in nondis-

eased primary human lung fibroblasts.

Fibroblasts were exposed to cigarette smoke-conditioned medium (10%

and 20% for 24 h). Proliferation was determined by [3H]thymidine incor-

poration. Protein expression levels were determined by immunoblotting

and translation was monitored using a translation control reporter sys-

tem.

Cigarette smoke significantly reduced fibroblast proliferation and signifi-

cantly upregulated fulllength C/EBPα and C/EBPβ proteins due to a shift

in the translational control of CEBPA and CEBPB mRNAs. This shift involved

the re-initiation of mRNA translation via the regulatory upstream open

reading frame, which coincided with increased interleukin-8 release and

a decrease in functional elastin level.

These findings provide a novel mechanism to understanding the tissue

remodelling observed in the lungs of COPD patients.

1 Pulmonary Cell Research, Dept of Biomedicine, and2 Dept of Thoracic Surgery, University Hospital Basel, Switzerland.

N. Miglino1, M. Roth1, D. Lardinois2, C. Sadowski2, M. Tamm1 and P. Borger1

Cigarette smoke inhibits lung fibroblast

proliferation by translational mechanismsN. Miglino*, M. Roth*, D. Lardinois#, C. Sadowski#, M. Tamm* and P. Borger*

ABSTRACT: Cigarette smoke is amajor cause of chronic obstructive pulmonary disease (COPD) and

emphysema. Although cigarette smoke represses cellular proliferation, the molecular mechanisms

underlying this phenomenon are unknown. CCAAT/enhancer-binding proteins (C/EBPs) are key

regulators of cell cycle progression, differentiation and pro-inflammatory gene expression, are

regulated predominantly at the translational level and may be involved in the pathogenesis of COPD.

The aim of this study was to assess the effect of cigarette smoke on proliferation and the expression

and translational regulation of C/EBPa and C/EBPb in nondiseased primary human lung fibroblasts.

Fibroblasts were exposed to cigarette smoke-conditioned medium (10% and 20% for 24 h). Pro-

liferation was determined by [3H]thymidine incorporation. Protein expression levels were determined

by immunoblotting and translation was monitored using a translation control reporter system.

Cigarette smoke significantly reduced fibroblast proliferation and significantly upregulated full-

length C/EBPa and C/EBPb proteins due to a shift in the translational control of CEBPA and

CEBPB mRNAs. This shift involved the re-initiation of mRNA translation via the regulatory

upstream open reading frame, which coincided with increased interleukin-8 release and a

decrease in functional elastin level.

These findings provide a novel mechanism to understanding the tissue remodelling observed in

the lungs of COPD patients.

KEYWORDS: CCAAT/enhancer-binding protein-a and -b, cell proliferation, chronic obstructive

pulmonary disease, human lung fibroblast, mRNA translation control, smoke

Chronic obstructive pulmonary disease(COPD) is characterised by chronic inflam-mation of the lung and airway remodel-

ling, leading to a fixed narrowing of the smallairways and destruction of the alveolar wall(emphysema). Cigarette smoke is the main riskfactor for the development of the disease [1]. COPDis a global health problem that affects .10% of theworld population over the age of 40 yrs [2]. Themost widely accepted hypothesis to explain thepathology of COPD and emphysema is an imbal-ance of proteases and their inhibitors, which leadsto the degradation of elastin and other structuralcomponents of the lung tissue [3, 4]. In anothermodel of the disease, the loss of tissue in end-stageCOPD (emphysema) may derive from an imbal-ance of tissue turnover when proliferation is unableto compensate for tissue loss [5].

Lung fibroblasts maintain the integrity of the lungparenchyma as they contribute to the repair of lunginjuries through synthesis and secretion of themain components of the extracellular matrix, such

as proteoglycans and collagens. Importantly, lungfibroblasts also produce elastin, an essential com-ponent of the alveolar extracellular matrix thatprovides the lung tissue with elasticity [6]. Animpaired capacity of lung fibroblasts to executetissue repair has been found in COPD patients [7].Cigarette smoke inhibits proliferation of normalfibroblasts [8], induces cellular senescence [9] andinhibits alveolar repair [5].

In the context of tissue maintenance and cellproliferation, CCAAT/enhancer-binding proteins(C/EBPs) could be of interest. C/EBPs have bothstimulatory and inhibitory effects on the prolifera-tion of many cell types and appear to be crucial forthe regulation of inflammatory responses. C/EBPsare an important family of transcription factors thatregulate cell differentiation, cell cycle progressionand the expression of many cytokines and chemo-kines relevant to COPD and emphysema [10, 11]. Inaddition, C/EBPb was shown to inhibit the trans-cription of elastin [12] and was elevated in emphy-sema lungs [13]. In airway smooth muscle (ASM)

AFFILIATIONS

*Pulmonary Cell Research, Dept of

Biomedicine, and#Dept of Thoracic Surgery, University

Hospital Basel, Basel, Switzerland.

CORRESPONDENCE

N. Miglino

Pneumology, Pulmonary Cell

Research, Dept of Biomedicine

University Hospital Basel

Hebelstrasse 20

CH-4031 Basel

Switzerland

E-mail: [email protected]

Received:

Nov 09 2010

Accepted after revision:

Aug 09 2011

First published online:

Aug 18 2011

European Respiratory Journal

Print ISSN 0903-1936

Online ISSN 1399-3003

Earn CME accreditation by answering questions about this article. You will find these at the back of the printed copy of this

issue or online at www.erj.ersjournals.com/misc/cmeinfo.xhtml

EUROPEAN RESPIRATORY JOURNAL VOLUME 39 NUMBER 3 705

Eur Respir J 2012; 39: 705–711

DOI: 10.1183/09031936.00174310

Copyright�ERS 2012

c


DBM Facts 2|2012 Department of BiomedicineDBM Facts 2|2012 Departement of Biomedicine

DEPARTMENT OF BIOMEDICINE ART 21

The Editorial Teamof DBM Factswishes all itsreaders nice

summer holidays!


22 EINTRIT TE | NEW COLLEAGUES DEPARTEMENT BIOMEDIZIN

Diego CalabreseHepatology

Ilona KrólHepatology

DEPARTEMENTBIOMEDIZIN

HEBELSTRASSE

Ronny NienholdExp. Hematology

DEPARTEMENTBIOMEDIZIN

KLINGELBERG-STRASSE

Jan SchulzCellular Neurophysiology

Marielle BrockhoffNeuromuscular Research

Sophia ThaneiClin. Immunology

Camille VivianiCellular Neurophysiology

Rubén LopezPerioperative Patient Safety

Ori RokachPerioperative Patient Safety


DEPARTMENT OF BIOMEDICINE EINTRIT TE | NEW COLLEAGUES 23

DEPARTEMENT BIOMEDIZIN HEBELSTRASSE

Maumita BhattacharjeeTissue EngineeringSilvana BöschImmunonephrologyLaura BinkertInner Ear ResearchAlessia RamseierInner Ear ResearchCorinna BildlAnimal Care

Sarah DimeloeImmunobiologyMarco FischerImmunobiologyAudrey FrachetSignalingNicholas SandersonClin. NeuroimmunologyOndrej StepanekTransplantation ImmunologySébastien WieckowskiCancer Immunology

DEPARTEMENT BIOMEDIZIN KLINGELBERGSTRASSE

Liyi LiCellular NeurophysiologyDieter KunzSynaptic Plasticity

Ausserdem haben angefangen:

Am 1. Juni 2012 hat Mike Abanto seine Tätigkeit als Biooptiker am DBM Hebelstrasse begonnen.

Mike hat an der Tufts University und der University of Utah in den USA studiert und anschlies-

send bei Pico Caroni am FMI promoviert. Die Mikroskopie ist sein Leben, man kann aber auch

sehr gut mit ihm über Rugby (das er professionell betrieben hat), Klettern, Bergsteigen, Ski-

fahren, Tauchen und was die Sportwelt sonst noch so hergibt philosophieren … Wir wünschen

Mike viel Erfolg und Freude bei seiner neuen Tätigkeit!

Heidi Hoyermann

Michael Abanto neuer Biooptiker

Die Arbeit läuft dir nicht davon, wenn du deinem Kind einen Regenbogen zeigst.Aber der Regenbogen wartet nicht, bis du mit der Arbeit fertig bist.

Unbekannt


24 BABYS DEPARTEMENT BIOMEDIZIN

CongratulationsDas DBM gratuliert ganz herzlich!

Mats Fritz KarowGeboren am 08.04.2012

Levi NeumannGeboren am 16.03.2012

Noah Pietro MiglinoGeboren am 18.04.2012


DEPARTMENT OF BIOMEDICINE BABYS 25

Herzlich willkommen,

allerseits!

Timothée CastetsGeboren am 12.03.2012


26 FREIZEIT / FREETIME DEPARTEMENT BIOMEDIZIN

TriathlonIt is hard to believe, but triathlon was only included as an “official” Olympic sport in 2000. As the Olympics are fast approaching, so is the anticipation of the 2012 gold medallists. The first Olympic winners of the mens’ and womens’ triathlon events were Simon Whitfield of Canada and Brigitte McMahon of Swit-zerland. Their performances on that day were a result of years of steady training and racing; they made tria-thlon look easy. However, most people see a triathlon and underestimate its difficulty. The arduousness lies in optimising each component so that there is no weakness in any one of the three events, and once optimised the ability to race at threshold level (or the point just below puking, in layman’s terms). Before I get into the specifics of triathlon I will give an overview of the general components of the sport first.

Triathlon consists of sequentially swimming, biking, and running without any breaks. The races range from 1–17 hours and there are four distances that competitors can participate in: a sprint distance (750

m swim, 20 km bike, 5 km run), Olympic distance (1.5 km swim, 40 km bike, 10 km run), half Ironman (1.9 km swim, 90 km bike, 21 km run), and full Ironman (3.8 km swim, 180 km bike, 42 km run). The momentary respite between events is called a transition and is known as the fourth stage of any triathlon. In the early development of a triathlete’s career these periods act as a momentary pause to catch one’s breath as the wetsuit is removed, the bike helmet is put on, and the shoes are changed. During the first couple of races of a triathlete’s career several minutes are lost, but by the time a competitor reaches an elite level, the racer will have perfected the first transition down to approximately 50 seconds and the second transition to 35 seconds.

A race at the amateur level will begin either at 7 or 8 on a Sunday morning. This is primarily so that that the bike course can be completed on “quiet” roads, or at least roads with very few cars on them. Prior to a race there is a buzz at the headquarters. Competi-

Swim start of Ironman Canada


DEPARTMENT OF BIOMEDICINE FREIZEIT / FREETIME 27

tors need to arrive at least 1.5 hours before the start to allow time to “check-in”, attach race numbers to race belts and bikes, find the area in race transition for the bike, lay-out all equipment that will be needed for the race, fill-up water bottles, attach timing chips to ankles, put-on the wetsuit, and then wait. Waiting is by far the most difficult aspect as nerves can take over, but generally the moment of anxiety is fleeting as races begin on time. However, there was one occa-sion that a race that I participated in was delayed by two hours because of fog on the water, this was the Ironman.

The Ironman is the biggest of the triathlon events and as Ironman triathletes like to say “it is a long day at the office’ since the race begins at 7 AM and finishes at midnight. Each event has a cut-off time; if one doesn’t complete the section in the allotted time then the competitor is asked to discontinue. The 3.8 km swim is given 2 hours and 20 minutes, although most athletes will complete this in approximately one hour. The bike portion must be completed by 5 PM the same day, meaning if one is a good swimmer one can use the “extra” time to complete the bike portion. Generally, the 180 km cycle course is com-pleted in 5-6 hours. The final 42.2 km marathon must be completed by midnight, or in the case of Ironman Switzerland, by 11 PM. The competitors crossing the line just before the cut-off time get as much cheering from the spectators as the race winners. I knew a competitor who crossed the line of Ironman France at 11:59:42 PM!

Preparations for these events usually begin up to a year in advance as one has to build up the training gradually. This is not only to prevent injury, but also to prevent mental burn-out from the sheer volume of training required. During this time one has to learn what it feels like to cope with tired muscles, constant hunger, and constant fatigue. In addition, it is impor-tant to practice “eating” while in constant motion. One might think that is a silly thing to practice, but funny things start to happen to the stomach after several hours of constant activity and finding foods/liquids/gels that do not give you a stomach ache is a feat in itself. In these types of races it is always important to

keep “the tank topped-up” meaning that if you find yourself hungry or thirsty you are closer to dehydra-tion than you think. You would be amazed how many competitors one sees after these races in the medical tents with i.v. drips attached to them!

The first time I participated in an Ironman was Iron-man Canada in 2001. Triathlon was becoming more popular and entrance to these races was becoming difficult to obtain. I had travelled out the year before to cheer on my friends in the race of 2000 so that I could be in line for the sign-up for the following year. The race of 2000 was memorable primarily because the day had started with hot, bright sunshine, but by the time the competitors had cycled to the moun-tain summit there was snow and medical tents were set-up for hypothermia. Seeing these events unfold showed me that partaking in this type of event should not be taken lightly.

The start time of Ironman Canada 2001 was 7 AM sharp, but the race officials wanted competitors to be there for a 6 AM race briefing and a 6:30 AM “lock-in”. This was a pen, by the water’s edge, where the competitors waited for the sound of the canons to start the race. Transition set-up for these big events is done the day before, so on race morning all I had to do was pump my tires, prepare my energy drink bottles, and make sure the clothing that I needed after each event was ready. The atmosphere was electric as the two thousand competitors with their friends and sup-porters were all there. Music was blaring, the sun was shining, and the anticipation was building. All of the year’s previous hard work was going to culminate in this race. It was going to be a good day!

Waiting for half an hour for the biggest race of your life is not easy, nor is it easy for the other 1999 competi-tors beside you. It is really important at the start of any Ironman to not swallow the lake water when there is a mass start. Can you guess why? The moment the canons sound a mob situation occurs. This is by far the scariest part of any Ironman because the more people around you in the water, the more kicking and punching that occurs. Goggles fly off, swimmers are pushed underwater; the whole process is scary. It is



important to keep calm and remain strong and always look for clear water. The buoys that signify the turn-around are usually at the other end of the lake and are difficult to find. Swimmers follow the feet of the per-son in front and this creates a massive vacuum that makes the swimming easier. Lifeguards in canoes signify the perimeter of the swim area. Reaching the turn-around point is also intense as many swimmers merge around one buoy. There are usually divers at these congestion points underneath the water to ensure that no one drowns. Once the congestion clears one just gets on with it and finishes swimming. By the time you see the shore you are ready for a change of activity.

Swimming continuously for over an hour can make one dizzy and at the exit of the swim there are people to help you keep your balance. First thing that many competitors do is guzzle a cola once the wetsuit has come off. This is not only for the sugar content, but the acidity does a pretty good job at killing anything that you may have swallowed in the water. You will never taste a cola as good as this in your life. Once changed, it is on to the bike for the next 5-6 hours.

The biggest problem with the 180 km bike course is boredom and coping with the numerous mood swings that one experiences while riding alone for many hours. At the beginning everything is new and invigorating because one is excited to be on the bike and not swimming! Unfortunately, by the fourth hour this novelty has worn-off. Your body hurts, you’re tired of the food that you are snacking on, and you keep asking yourself “why am I doing this?” However, despite that, Ironman racing is a fantastic way to see a country and these bike courses have allowed me to see places of Canada, Switzerland, UK, and Austria that I never would have seen otherwise.

The last 20 km of the bike are generally the hardest, but in the case of Ironman Canada it was all downhill. We had three mountains to climb on that course and that had taken some of the monotony out of being on the bike for so long. I was riding slower than the men I had been training with, but several had to stop or drop-out because of bike mechanical issues that had been caused because of a vandal who decided to put tacks on the road. One has to be prepared not only for the proper functioning of your own body, but that of

Bike transition of Ironman Canada



your bike as well. There are “feed” stations along the course consisting of bags that have been pre-packed by yourself for food that you may need at the halfway point of the bike. There is also a “mechanical” van that drives around the course, but with hundreds of competitors to look after it is often quicker to repair your own flats or broken chains.

Arriving into transition for the marathon is exciting. Like the swim, one is very happy to get-off the bike and have a change in activity. Crowds are cheering and this is usually the time when the first male pro is finishing the run. It is a bit disheartening when one sees the race winner finishing the marathon when one is just about to begin it. Like the biking section, the first half of the marathon is fun. There are lots of people around and one can usually pair up with other runners for support; this removes some of the bore-dom. In addition, the feeding stations along the run route also have tonnes of supporters to encourage the runners. In the case of Ironman Canada, the run was along a lake. It was an out-and-back so you could see exactly how close your nearest competitor was. When I started the marathon it was 35°C without any

shade. It was imperative to be shielded from the sun, reapply sunscreen, and be constantly hydrated. The most difficult part was the last 10 km. I could smell greasy fries and all I wanted was to taste some. This was also the point at which I saw Sister Madonna Buder who is also known as the “Iron Nun”. At the time she was a 71 year old multiple Ironman record holder for her age group and it was remarkable to see someone that age participating in this event.

By the last 2 km I heard the cheers of the crowd that spurred me on to finish the race. In Ironman it doesn’t matter if you finished first or last; the crowd cheers each competitor the same. As I approached the last kilometre I saw my family and friends cheering me and heard the announcer say “Congratulations! You are an Ironman!” After crossing the finish line everyone is quickly given a medical check and then whisked away for a massage and pizza. The soreness and tiredness remains for a few weeks as well as the hunger, but in the end it is all worth it because you are an Ironman!

Brynn Kvinlaug

Race winner of Ironman Canada


30 SEASON DEPARTEMENT BIOMEDIZIN

Wien ist andersEs ist Freitag, 14.00 Uhr – endlich Wochenende, nichts wie raus aus dem Büro. Ich lasse in gutem Wiener Stil alles stehen und liegen – eine der ersten Fertigkeiten, die ich hier gelernt habe. Es gibt nichts, aber auch gar nichts, was nicht warten könnte bis Montag. Nur keinen Stress aufkommen lassen, das wird sich schon auch noch nächste Wochen ausge-hen. Jetzt erst mal ins wohl verdiente Wochenende: Ausspannen, Geniessen. Eine Freundin aus der Schweiz hat sich angekündigt. Wir werden einige ihrer Lieblingsbeisln und -orte unsicher machen, auf jeden Fall viel essen und trinken, wir sind schliesslich in Wien, wo das zu (fast) jeder Tages- und Nachtzeit in über 4000 Lokalen in 23 Bezirken möglich ist.

Endlich ist der lang ersehnte Frühling da. Ich schlendre vom Büro in der Gonzagagassen durch den Tiefen Graben Richtung Freyung in der Wiener Altstadt zu einem meiner vielen Lieblingsschani-gärten. Nach endlosen Winterwochen wolkenver-hangenen Himmels sauge ich die Sonnenstrahlen dieses warmen Tages in mich auf. In der Trafik ums Eck kaufe ich die neueste Wochenausgabe des Fal-ters für die Übersichtsliste mit dem Veranstaltungs-programm der Stadt und die fachkundigen Artikel und Kommentare zu den neuesten Politskandalen.

Obwohl die Bedienung im Kaffeehaus im Schotten-stift wie hier vielerorts nicht zu gebrauchen ist, lockt der ruhige Gastgarten im Hinterhof. Ribisel- und Mohntorten zählen zu den besten der Stadt, und das entschädigt fast für das schlamperte Personal. Ich sitze vor einer Melange mit Milchschaum anstelle des traditionellen Schlagobers und lese kopfschüt-telnd im Falter über eine Staatsanwaltschaft, die der Bundesjustizministerin weisungsunterstellt ist; über im Ministerium liegen gebliebene oder verlo-ren gegangene und dadurch verjährte Beweisakten im Zusammenhang mit brisanten Politikeraffären

der letzten Jahre; über die Lockerung des Anti-Korruptionsgesetzes, damit Geschäftsgeschenke, wie Eintrittskarten zu den Salzburger Festspielen, wieder verschickt werden können; über die For-derung der Kritiker nach mehr Rechtsstaatlichkeit. Österreich ist eine Bananenrepublik, die mit Vor-liebe Freunderlwirtschaft betreibt; und die Wiener betonen immer wieder, dass in ihrer Stadt der Bal-kan anfängt.

Spätestens jetzt bin ich reif für einen Almdudler, oder vielleicht doch eher einen Radler oder Aperol Spritz. Dafür schau ich, ob im Café Korb um diese Zeit noch ein Tisch zu ergattern ist. Auf jeden Fall

Hofburg


DEPARTMENT OF BIOMEDICINE SEASON 31

muss ein Schoko-Palatschinken her. Aber vorher könnte ich jetzt eigentlich noch einen Zwiebelrost-braten mit Nockerln und dazu ein Achterl Veltliner nehmen. Oder doch ein Gulasch mit Knödln, Eier-schwammerln oder Fleckerln? Wiener Schnitzel geht eh immer.

«Wie wär’s mit einem Eis beim Bortolotti in der Mariahilfer Strasse?», fragt meine Freundin, «Ich fahr mit einem City Bike rüber.» Sie sitzt im CAT auf dem Weg vom Flughafen Schwechat in die Stadt. Da ich draussen im 17. Bezirk wohne, logiert sie lieber in ihrer heiss geliebten grosszügigen Ferienwoh-nung, die eine Wiener Freundin von mir vermietet - eine traumhafte typische Wiener Altstadtwohnung mit Blick auf den Prater und das Riesenrad, ein Kat-zensprung vom Zentrum entfernt. «Wir könnten ausgiebig Shoppen, beim Café Ritter reinschauen, runter ins MuseumsQuartier, vielleicht ins Glazis, gehen. Und falls wir dann noch Lust haben, im Bohème am Spittelberg ein paar Arien reinziehen.» Das tönt nach einem gut Wienerischen Samstags-programm. Abends beglücken wir dann die Bon-bonniere Bar, die Wein-Bar beim Rathaus und die Urania-Bar und enden auf dem Weg nach Hause im 2. Bezirk im Künstlerviertel um den Karmeli-termarkt auf ein Fluchtachterl im Skopik & Lohn, bevor wir völlig erschöpft in die Federn sinken.

Da das sommerliche Wetter anhält, ist Auskatern im geräumigen Schanigarten des Café Dommayer angesagt – die Adresse für die besten Kuchenstücke in ganz Wien. Wir befinden uns im distinguierten teuren grünen 13. Aussenbezirk Hietzing – ein Dorf in der Stadt, wie eigentlich jeder Bezirk in Wien ein Dorf – ein Grätzel – mit ganz eigener Atmosphäre, typischen Bewohnern und Gepflogenheiten ist. In Hietzing trifft sich die Wiener High Society und wer gern dazu gehören möchte; man ist hier wer und zeigt es offenherzig mit viel Nerz und Klun-kern. Ich verschlucke mich fast, als zwischen all den Schickimickis, dem Herrn Hofrat, der Frau Ober-studienrätin und dem Mag. Dr. XY, plötzlich die Literaturnobelpreisträgerin, Elfriede Jelinek, per-sönlich an unserem Tisch vorbeischwebt mit der ihr eigenen Eleganz, die so weit entfernt ist vom

Wiener hoch gestylten Frauendurchschnitt. Meine Freundin erblasst ehrfürchtig und findet es einfach leiwand in dieser dörflichen Weltmetropole.

Kein Hietzing-Besuch ohne ein dunkles Seidel beim Brandauer. Wir schauen amüsiert zu, wie die Pief-kes am Nachbartisch genüsslich eine der grössten Portionen Spare-Ribs der Stadt verzehren. Seit ich hier lebe hat sich mein Fleischkonsum mindestens verdoppelt und ist im Vergleich zu einem Wie-ner immer noch eher bescheiden. Am Nebentisch zur andern Seite jammern schlecht gelaunte Wie-ner über die Kürzung der Mindestsicherung. Tat-sächlich gibt es jetzt anstatt 855 nur noch 773 Euro monatlich – das Ganze bei einer Armutsschwelle von 1’031 Euro und Arbeitslosigkeit von 9%. Meine Freundin kann das fast genauso wenig glauben wie die Tatsache, dass durch alle Bildungsschichten der durchschnittliche Gehaltsunterschied zwischen Männern und Frauen bis zu über 50% betragen kann. Zudem sitzen nur gerade 13% der Frauen in Führungspositionen mit Entscheidungskompe-tenzen. Und noch weniger glaubt sie, dass sie für den gleichen Job in der Schweiz mindestens das Doppelte bis fast Dreifache verdient.

In der Ausgangspassage des Brandauers locken die Schlossstubn und ein gutes Glasl Prosecco

Riesenrad


32 SEASON DEPARTEMENT BIOMEDIZIN

direkt vom Fass. Weil das so spottbillig ist, bleibt es natürlich nicht bei dem einen. Amüsiert beobach-ten wir die aufgedonnerten Wasserstoffblondinen mit den Versace-Handtaschen auf den Barhockern, die sich von ihren ausgedehnten Shopping-Trips erholen und schon mal auf den Abend einstim-men. Im Verlauf der nächsten Stunden werden sich hier Szenen abspielen, die man sonst nur in Soap Operas zu sehen bekommt: Leute werden sich furchtbar betrinken, die Ladies werden auf ihren High Heels nur mit Mühe und wenig graziös zur Toilette schwanken. Paare werden sich formieren, unverhohlen anfangen, miteinander zu flirten und schliesslich zu knutschen, um sich kurze Zeit später neu zu formieren. Ganze Beziehungsdramen wer-den inszeniert, angestachelt von Neid und Rachege-lüsten. Beste Freundinnen spannen sich die Männer gnadenlos vor der Nase aus. Der Speichelaustausch gewisser Personengruppen in dieser Bar kann an einem Abend enorm sein. Wiener Mann und Frau genieren sich wenig, man sieht das nicht so eng und nimmt es noch weniger ernst. Wien ist freizügig – nicht nur am stadteigenen FKK-Strand entlang der Donau.

Wir lassen den Tag mit einem Spaziergang im nahen wunderschönen weitläufigen Schlosspark von Schönbrunn ausklingen. Die Zeit reicht wie-der einmal nicht fürs magische Palmenhaus und auch nicht für den Tierpark. Wir lassen den Abend ausklingen mit dem Blick über die Stadt vom Gar-ten der Villa Aurora aus, vor uns auf den Tellern Cordon bleus mit griechischer und asiatischer Füllung, gefolgt von einem Kaiserschmarrn. Bald schon heisst es Abschied nehmen und in dem bin ich schon ganz gefühlsbetont wienerisch: Es geht fast nicht, es bricht mir das Herz. Fremde brauchen eine Weile, bis sie in Wiener Herzen aufgenommen werden, aber wenn sie mal drin sind, gibt es kein Entrinnen mehr. Mein Abschiednehmen dauerte nach zwei Jahren in Wien doppelt so lange als beim Wegzug von Basel von all meinen Freunden und Bekannten, die ich schon seit Urzeiten kenne. Spä-testens seither weiss ich: Wien ist einfach anders! Denise Berger

Texterklärungen und Anmerkungen:

Allgemeines:

etwas geht sich aus: etwas lässt sich (zeitlich) erledigen

Beisl: Kneipe

Wien hat 23 Bezirke, alle mit eigenem Bezirkswappen und Geschichte: www.wien.gv/at/bezirke/bezirkswappen; sie sind ungefähr kreisförmig im Uhrzeigersinn um die Stadtmitte ange-legt, 21. und 22. Bezirk liegen über der Donau im Nordosten; die Nummern in der Postleitzahlmitte zeigen jeweils den Bezirk an: 1010 = 1. Bezirk, 1130 = 13. Bezirk etc.

Trafik: zu vergleichen mit unseren Kiosk-Läden, haben ein ähn-liches Warenangebot; gibt es an vielen Strassenecken, oft direkt auch bei Eingängen der U-Bahnstationen auf der Seite (oft so klein, dass man sie fast übersieht). Dort bekommt man auch Parkscheine.

Falter: linksliberale Wochenzeitung mit detailliertem Veranstal-tungsprogramm für Wien und Umgebung; sehr guter, hochste-hender investigativer Journalismus, Mitbegründer und Chefre-dakteur: Armin Thurnher.

Schanigarten: vor den Gastronomiebetrieben auf dem Trottoir (Gehsteig) aufgestellte Tische und Stühle oder ein Gastgarten im Hinterhof; die verordnete Schanigartensaison läuft max. vom 1. März bis 15. November

Schlampert: österr. abwertend gebraucht für: nicht sorgfältig, ungenau, nachlässig

Rathaus


DEPARTMENT OF BIOMEDICINE SEASON 33

bau), Tel. 01 5265660; in diesem 7. Bezirk tummeln sich zwischen MuseumsQuartier, Spittelberg, Neubaugasse und Urban-Loritz-Platz die jungen Kreativen, Selbstständigen und Studierenden: Man nennt das Neubau-Grätzel der neuen Bourgeois Bohemi-ans daher auch Boboville.

Edelbeisl Bohème, Spittelberggasse 19, 7. Bezirk (Neubau), Tel. 01 5233173, mit viel Opernmusik als Beschallung und signierten Starfotos an den Wänden

Beisl und Bar Skopik & Lohn, Leopoldsgasse 17, 2. Bezirk (Leo-poldstadt), Tel. 01 2198977

Brandauers Schlossbräu, Am Platz 5, 13. Bezirk (Hietzing), Tel. 01 8795970

Beisl Villa Aurora: Wilhelminenstr. 237, 16. Bezirk (Otlakring), Tel. 01 489 33 33, durchgehend warme Küche, beste Cordon bleus der Stadt mit kreativen Füllungen. Der Ausblick über die Stadt lohnt sich.

Kaffeehäuser:

In Wiener Kaffeehäusern sitzt man für gewöhnlich lange und ausgiebig, studiert die aufliegenden Zeitungen, liest Bücher oder betätigt sich als Schriftsteller, ohne besonders viel konsu-mieren zu müssen. Neben viel Kaffee wird meist durchgehend traditionelle Wiener Küche serviert. Eine sehr kleine Auswahl:

Café im Schottenstift, Schottengasse 2, 1. Bezirk (Innere Stadt), Tel. 01 535155013

Künstlercafé Korb, Brandstätte 9, 1. Bezirk (Innere Stadt),Tel. 01 5337215

Café Ritter, Mariahilfer Strasse 73, 6. Bezirk (Mariahilf),Tel. 01 587 82 38

Café Dommayer, Dommayergasse 1, 13. Bezirk (Hietzing),Tel. 01 87754650

Bars:

Bar Schlossstubn, Am Platz 2, 13. Bezirk (Hietzing), Nähe Sei-tenausgang Schlosspark Schönbrunn - preiswertester guter Pro-secco vom Fass, Glas 1.80 Euro

WIENO: Wiener Weinbar, neben Rathaus in Lichtenfelsgasse 3, 1. Bezirk (Innere Stadt), 60 Weine von 18 Wiener Winzern (es gibt Rebberge mitten in und um die Stadt herum, am besten unternimmt man eine Wanderung: http://www.wien.gv.at/umwelt/wald/freizeit/wandern/wege.html)

Bar Urania, Uraniastrasse 1, 1. Bezirk (Innere Stadt),Tel. 01 7133066

Pianobar Bonbonniere, Spiegelgasse 15, 1. Bezirk (Innere Stadt), Tel. 01 512 68 86, älteste Bar im Herzen von Wien mit Original-ausstattung der 20er Jahre, mit Live-Klaviermusik

Buchtipp für politisch Interessierte: Michael Fleischhacker, «Politikerbeschimpfung», 176 Seiten, 22,00 Euro, ISBN: 978-3-902404-63-3

Anreise Flughafen-Stadtzentrum:

CAT: Mit Airport Shuttle direkt vom Flughafen Schwechat in 16 Minuten zur U-Bahnstation «Wien Mitte/Landstrasse», umstei-gen auf U3 Richtung Ottakring zum Steffl (Stephansdom) für 9 Euro die Einzelfahrt. Wer trotzdem lieber mit dem Taxi fährt, ruft Josef Haager an: +43 664 785 28 64.

Empfohlene Unterkunft: preiswerte wunderschöne Ferien-wohnungen von Susanne Tiefenbrunner direkt beim Prater, Ausstellungsstrasse 31, 1020 Wien,Mobil-Tel. +43 699 195 80 151,http://www.apartment.at/print/apartment/115

City Bike: www.citybikecard.at, es gibt viele über die Stadt ver-teilte Veloparkings mit Fahrrädern zum Ausleihen: 1. Stunde gratis, Tourist Card pro Kalendertag: 2 Euro; unbedingt sichere Fahrradrouten im Internet auskundschaften, da Radfahren in Wien ziemlich gefährlich sein kann. Die Autofahrer ignorieren Fahrradfahrer aus Prinzip - gilt übrigens auch umgekehrt.

Das Verwenden von akademischen Graden und Titeln jegli-cher Art kaschiert im konservativ-bürgerlich geprägten, wenig demokratisch orientierten Österreich die eigene Mediokrität und befriedigt die Eitelkeiten und basiert wohl auf einem tief sitzenden Minderwertigkeitskomplex. Üblich ist die unlogi-sche aufsteigende Reihenfolge, weil man keinen Titel weglassen möchte (Mag. Dr. XY) und die Verdopplung mit englischen Titeln am Schluss, wobei das für die so wichtige mündliche Anrede völlig ungeeignet ist. Gutes, durchaus realistisches und ernst gemeintes Beispiel: HR Univ.-Prof. Akad. Tourismusmanagerin Dr.phil. Maria Bauer, BSc MSc, will heissen: Frau Bauer ist Hof-rätin, Universitätsprofessorin, hat einen Unilehrgang zur Tou-rismusmanagerin sowie ein Doktorratsstudium, Bachelor- und Masterstudium absolviert. Zaghafte Emanzipierungsversuche zeigen sich in den weiblichen Formen wie Maga. für Magistra und Dr.in für Doktorin. Bachelor- und Masterabgänge sind trotz Bologna-Reform ganz frische «Babies» an den Universitäten und noch arg gewöhnungsbedürftig.

Leiwand: super

Piefke: abwertend gemeinte Bezeichnung für Deutsche, die in Österreich einen schweren Stand haben; im Vergleich dazu haben die Schweizer von vornherein einen Sympathiebonus und sind gern gesehen.

Kulinarisches:

Getränke:

• Almdudler: österr. Kräuterlimonade• Radler: Biermischgetränk aus Bier und (Zitronen-)Limonade, bei uns Panaché genannt • Aperol Spritz: erfrischender fruchtig-bitterer Aperitif-Likör, der mit Prosecco oder Weisswein gemischt wird• G’spritzter: Wein und Sodawasser• Achterl, Vierterl: Weinglasgrössen, als Fluchtachterl oder -vierterl wird das Glas vor dem Nachhause-Gehen bezeichnet • Wiener Melange: wird traditionell in einem hohen Stielglas serviert und besteht zu zwei Dritteln aus starkem schwarzem Bohnenkaffee und zu einem Drittel aus heisser Milch. Die Milch darf aber nicht gekocht sein. Darauf kommt eine grosszügige Portion Schlagrahm (Schlagobers), die mit etwas feingemahle-nem Kaffee bestreut wird.• Seidel: kann sich auf Bier und Wein beziehen, etwa 0.354 Liter

Essen:

• Ribisel: Johannisbeere• Palatschinken: Pfannkuchen mit verschiedenen Füllungen• Eierschwammerl: Pilzsorte• Knödl: geformte Teigkugeln aus verschiedensten Grundzu-taten (z. B. zerquetschte Kartoffeln, altbackenes Brot, Quark, Grieß), die in siedendem Wasser gegart werden und als deftige Beilage, Suppeneinlage oder süße Nachspeise gegessen werden• Fleckerl: Nudeln• Nockerl: Spätzle• Kaiserschmarrn: Pfannkuchenähnliche Süssspeise, serviert mit Zwetschkenrösta (=Pflaumenkompott)

Gelateria Paolo Bortolotti: bestes Eis der Stadt; entlang der Mariahilfer Strasse (Shopping-Strasse im 6. Bezirk) gibt es 3 Geschäfte, unbedingt das Mohneis probieren!

Restaurant Glacis im MuseumsQuartier oberhalb des MUMOK (Museum Moderner Kunst), Museumsplatz 1, 7. Bezirk (Neu-



UrlaubslektüreJosé Saramago: Das Zentrum(Rowohlt, gebunden, 22.90 Euro)

Die ersten Zeilen höre ich mitten aus dem Buch he-raus. Als mein Mann mir, der das Buch gerade liest, für mich völlig aus dem Zusammenhang gerissen, wenige Zeilen vorliest, in denen ein Hund mit einer unglaublichen Einfühlsamkeit in die Geschichte ein-geführt wird. Später nehme ich mir das Buch und lese die erste Begegnung des alten Töpfers Cipriano Al-gor, der Hauptfigur des Buches, mit dem zugelaufe-nen Hund, der später Achado heissen wird, zu Ende. Ich bin elektrisiert von dieser Art des Erzählens, von dieser Kunstfertigkeit des Schreibens, fasziniert, wie Saramago es schafft, mich innerhalb von wenigen Zeilen, in die Hundehütte eines offenen Hofes einer kleinen Töpferei zu versetzen, in der der alte Cipria-no Algor am Rande eines portugiesischen Dörfchens

Kafka on the ShoreIf you like fiction, fantasy, mystery, original ideas and an unpredictable plot, then you will probably enjoy Haruki Murakami’s novel. You will enter into a unique dream-related atmosphere. Kafka on the Shore is an amazingly imaginative story compris-ing two distinct but interrelated plots, the life of a 15-year-old teenager Kafka and that of an old illit-erate man, Nakata. Both characters have their own quest (or are they the same?), both are trying hard to escape their fate.

Kafka runs away from his father's house to escape an oedipal curse and to go in search of his mother and sister, while the police begin inquiring after him in connection with a brutal murder.

Nakata, who has experienced a strange traumatic event in his childhood, lost many of his mental facul-ties but in their place is able to talk to cats. He knows he has a mission, ignores which one, but when the

time comes he will know exactly what to do.

In this novel, fishes fall from the sky, people collect cats’ souls, WWII sol-diers appear from forests, people commit murder and then are unsure if they commit-ted it. Murakami mixes suspense, humour and refers all the time to both the real and the surreal so that you are not sure which world you are in.

Murakami’s metaphoric writing is all about human condition and the (non)sense of life. As so, Kafka on the Shore poses more questions than he answers, creates more puzzles than he solves. And it is just fun! Let your imagination combine several of these riddles and finish the story any way you wish. Bon voyage!

Anne-Catherine Feutz

seinem Handwerk nachgeht. Keine Bange, dieses Buch ist nicht sen-timental. Es ist auch keine dog-matische Auseinandersetzung des Marxisten Saramago mit dem The-ma Arbeit. Es ist die einfühlsam erzählte Geschich-te eines alten Töpfers, der seine Waren irgendwann nicht mehr dem hypermodernen Einkaufszentrum verkaufen kann, da Plastik besser als Ton zu sein scheint. Eines alten Töpfers, der sich auf seine Weise dagegen wehrt. Ein Buch nicht nur für den Portugal-urlaub, sondern für alle, die nach den Ferien zurück in ihr «Zentrum» gehen.

Heidi Hoyermann



Room by Emma Donoghue“Jack is five, and excited about his birthday. He lives with his Ma in Room, which has a locked door and a skylight, and measures eleven feet by eleven feet” (at just under 3 metres by 3 metres, that’s small!) “He loves watching TV, and the cartoon characters he calls friends, but he knows that nothing he sees on screen is truly real – only him, Ma and the things in Room. Until the day Ma admits that there’s a world outside.”Having read the above blurb on the back of the book, I decided that this was not a book I would ever want to read. So what if it was a runner up for the Mann Booker prize (the UK’s major book award) in 2011? It looked as if it was going to be 320 pages on a hor-rible theme that I would find far too distressing. Yet I did read Room and now I’m recommending it to you as a summer read, and even an on the beach read! I was “persuaded” to try the first couple of chapters

Have you been to Hyperion?Dear DBM reader, let me start with a question. Do you like books AND science fiction? Are you desperately looking for a sense of wonder, that precious feeling invoked by the sudden understanding of new concepts & ideas? If your answer is YES, than I may have the right book for you. It is the classic novel Hyperion written by Dan Simmons. The story is set in a far-future galaxy where humanity is scattered across hundreds of worlds, following the “Big Mistake” which destroyed Old Earth, all con-nected by wormhole technology and united under the Hegemony. This vast empire is under threat by the Ousters, interstellar rebel humans mutated beyond recognition, who dwell free of and beyond the bounds of the Hegemony. On the eve of galactic war, the book follows the journey of seven pilgrims (the Priest, the Soldier, the Poet, the Templar, the Detective, the Con-sul, the Scholar and his little daughter) who are trav-elling on Treeship Yggdrasill to the distant planet Hyperion in order to visit The Time Tombs (ancients structures that move backwards through time), con-front their deadly guardian (a mysterious creature known as The Shrike) and hopefully help to pre-

and keep an open mind, and I re-luctantly agreed. Once I started reading, I wanted to finish the book in one sitting. It made me smile, then made me weep and then made me smile again. I was devastated and then uplifted and can’t remember when a book last took me on such a rollercoaster ride. It’s also written in straightforward English sentences and so just flowed along. “When it’s over you look up: the world looks the same but you are somehow differ-ent and that feeling lingers for days,” commented one reviewer and she’s absolutely right.Written in Jack’s voice, Room is the story of a mother and son whose love lets them survive. As it’s difficult to say much else without spoiling the plot, I’ll just say “this is definitely one you should read.”

Hilary Ireland

vent the total destruction of human civilization. During the journey, the pilgrims tell the stories of their lives. Each tale has an extremely different mood and atmosphere, giving the entire book a beautiful, patchwork sort of feel. The stories contain first con-tact mission, military SF, literary symbolism, colonial rebellion, cyberpunk, hard-boiled detective story, a touch of horror, and beautifully written stories of per-sonal tragedy. This is not a collection of unrelated tales. Far from it. After the first few stories you will start to see deeper patterns and sense the hidden forces coming together. You will witness the effects of one story on another and feel the storm gathering. And most of all, you will begin to understand that Hype-rion is the one wild card which could shift the balance of mankind's fate one way or another, and somehow these pilgrims hold the key...I have nothing left to say. See for yourself. Take this book, turn the first page and start your pilgrimage.

Lucia Kubovcakova


36 INFORMATIK / INFORMATICS DEPARTEMENT BIOMEDIZIN

Einbau Kit um das optische Laufwerk durcheine 2. Harddisk oder SSD zu ersetzen

LMP Disk Doubler ist ein Konverter (Einbau-) Rahmen für MacBook und MacBook Pro Unibody, um anstelle desoptischen Laufwerks eine zweite SATA Harddisk oder zusätzlich eine SSD einzubauen. Fast alle MacBook undMacBook Pro Unibody werden unterstützt.

Eine empfehlenswerte Konfiguration ist eine super schnelle SSD (500 MB/Sek. mit SATA 6 Gb/s SSD der neuestenGeneration) mit einer standard Harddisk zu kombinieren. Oder die Kapazität durch zwei 1 TB Harddisk auf maxi-male 2 TB zu erweitern und eine Harddisk als Time Machine Backup zu verwenden. Auch eine Datenspiegelungmit dem Apple System Utility wird dadurch möglich.

Das ausgebaute DVD Laufwerk kann in ein preisgünstiges USB Gehäuse eingebaut werden. Damit steht dasDVD Laufwerk auch nach Ausbau extern zur Verfügung.

LMP Disk Doubler

• Konverter (Einbau-) Rahmen für weitere Harddisk oder SSD(2.5” SATA HDD/SSD, 9.5 mm Bauhöhe, ersetzt optisches Laufwerk)

• Alle MacBook und MacBook Pro Unibody Modelle (ab Late 2008)

• SSD 6 Gb/s (500 MB/Sek. Datendurchsatz) anstelle der Harddisk installieren und dann diese Harddisk anstelledem optischen Laufwerk (nur SATA Anschluss der internen Harddisk hat 6 Gb/s Interface)

• Installations-Werkzeug im Lieferumfang enthalten.

• Der Einbau durch einen Apple Techniker dauert ca. 30 Minuten.

Artikel Enduser CHF8% MWSt

LMP Disk Doubler, Einbau Kit für 2. Harddisk/SSD (2.5”; statt DVD Laufwerk)für alle MacBook & MacBook Pro Unibody 9414 68.–

LMP Gehäuse für DVD Laufwerk aus MacBook, MB Pro Unibody & Mac mini, USB 2.0 9413 38.–

LMP Disk Doubler Bundle, Kit für 2. HD/SSD (statt DVD) MacBook & MB Pro& externes USB-DVD Gehäuse [Art. 9414 & 9413] 9415 98.–

LMP Disk Doubler für MB & MacBook Pro

Disk DoublerKonverter (Einbau-) Rahmen

Gehäuse (5.25”) fürDVD Laufwerk, USB 2.0

Distribution: Cropmark AGJurastrasse 56, CH-5430 WettingenFon +41 (0)56 437 60 70, Fax +41 (0)56 437 60 77www.cropmark.ch, [email protected]

cropmark ag

2.01, 6/2012, CH

News from the DBM-iT

EndNote X5Infolge der Kooperation zwischen der Uni und den USB kann EndNote als Lizenz für 30.00 CHF bezogen werden. Die aktuelle Version heisst X5 und ist für OSX 10.6/10.7 und für Windows7/Vista/XP verfügbar.PRISM und FlowJo Sobald wir unsere neuen iMac's erhalten, werden wir FlowJo und PRISM auf den öffentlichen iT Rechnern im 3.OG des ZLF installieren. Somit können dort auch diese

CD/DVD-Drives werden immer seltener benötigt. Gehören Sie auch zu den Benützern die nur einmal im Quartal eine CD lesen müssen? Dann haben wir etwas, das Sie sich

beiden Programme benützt werden.Weiterhin ist auch das gesamte Adobe Creative Suite installiert.Umbauaktion

anschauen oder bestellen sollten.

Zur Zeit können wir die aufgeführten SSD 2.5" Drives zu folgenden Preisen bestellen:•120 GB OCZ Agility3 SSD MLC SATA, 6 Gb/Sek,, 500Mb/Sek. 130.00•240 GB OCZ Agility3 SSD MLC SATA, 6 Gb/Sek,, 500Mb/Sek. 265.00•480 GB OCZ Agility3 SSD MLC SATA, 6 Gb/Sek,, 500Mb/Sek. 635.00Rechenbeispiel:Sie wollen die interne bestehende HD weiterhin benützen und zusätzlich noch das interne DVD Laufwerk in ein externes USB2.0 Gehäuse umbauen lassen? Dann wählen Sie eine der obigen SSD Platten und addieren die 98.00 CHF dazu.Sollten Sie Interesse an einer solchen Lösung haben, so fragen Sie uns einfach an. Anfagen bitte an [email protected] oder an [email protected] mit dem Betreff "DiskDoubler Umbau".


… erfahren wir von Verdon Taylor mehr über Neuronal Stem Cells

… führt uns Nicole Schaeren-Wiemers in die Welt der Neurobiology ein

... lernen wir mit Michael Abanto,worauf es beim Rugby ankommt

… lassen wir den Sommer Revue passieren mit den schönsten Fotos vom DBM Barbecue

… entführt uns Arun Cumpelik in seine Heimatstadt Prag

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ROSstabilization

PI3K

NO

IFN

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IFN-

TNF-

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IL-4

IL-4 /

13 R

JAK1 / 3

P

STAT6 P

PP

STAT6

STAT6

- “Th2 response”- response to oxidative stress- neuroprotective mechanism- anti-apoptotic mechanisms

Ausfahrt

Berggipfel erglühen,Waldwipfel erblühenVom Lenzhauch geschwellt;Zugvogel mit SingenErhebt seine Schwingen;Ich fahr’ in die Welt.

Mir ist zum GeleiteIn lichtgoldnem KleideFrau Sonne bestellt;Sie wirft meinen SchattenAuf blumige Matten;Ich fahr’ in die Welt.

Mein Hutschmuck die Rose,Mein Lager im Moose,Der Himmel mein Zelt;Mag lauern und kauernWer will, hinter Mauern;Ich fahr’ in die Welt.

Joseph Victor von Scheffel (1826–1886)

30 34 · michael abanto verstärkt seit dem 1. juni 2012 die biooptik-facility an der hebelstrasse!...

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